Chapter Navigation
- Neurotransmitters and central nervous system PH1.19
- Sedatives and hypnotics PH1.19
- Benzodiazepines PH1.19
- Barbiturates PH1.19
- Nonbenzodiazepine hypnotics PH1.19
- General anaesthetics PH1.18
- Local anaesthetics PH1.17
- Alcohols (ethanol and methanol) PH1.20
- Antiepileptic drugs PH1.19
- Generalized seizures
- Partial seizures
- Chemical classification of antiepileptic drugs
- Clinical classification of antiepileptic drugs
- Mechanism of action of antiepileptic drugs ( fig. 5.8A and B)
- Newer antiepileptics
- Analgesics
- Opioid analgesics PH1.19
- Antiparkinsonian drugs PH1.19
- Classification
- Dopamine precursor: Levodopa
- Peripheral decarboxylase inhibitors: Carbidopa and benserazide
- Dopamine-receptor agonists: Bromocriptine, ropinirole and pramipexole
- COMT inhibitors: Tolcapone, entacapone
- MAO-B inhibitors: Selegiline (deprenyl) and rasagiline
- NMDA-receptor antagonist: Amantadine
- Central anticholinergics
- Classification
- Drugs for Alzheimer’s Disease
- Cognitive enhancers (nootropics) PH1.19
- CNS stimulants PH1.19, PH1.22
- Psychopharmacology PH1.19
- Antipsychotic drugs PH1.19
- Antianxiety agents PH1.19
- Antidepressants PH1.19
- Drugs for bipolar disorder PH1.19
Book Chapter
Drugs acting on central nervous system - Pharmacology for Medical Graduates, 4th Updated Edition
Pharmacology for Medical Graduates, 4th Updated Edition, CHAPTER 5, 164-229
Neurotransmitters and central nervous system PH1.19
Neurotransmitters in CNS
Neurotransmitters in the central nervous system (CNS) could be inhibitory, excitatory or both ( Fig. 5.1 ).
Inhibitory postsynaptic potential (IPSP)
When an inhibitory transmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to K + or Cl − increases ( Fig. 5.2 ).
Excitatory postsynaptic potential (EPSP)
When an excitatory neurotransmitter binds and interacts with specific receptors on postjunctional membrane, the membrane permeability to cations increases ( Fig. 5.3 ).
Manifestations of CNS depression and stimulation
| CNS depression | CNS stimulation |
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Sedatives and hypnotics PH1.19
Sedative is a drug that reduces excitement and calms the person. Hypnotic is a drug that produces sleep-resembling normal sleep.
Sleep
The phases of sleep include nonrapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. NREM sleep is divided into the following stages: 0, 1, 2, 3 and 4. Normally, about 50% of sleep time is spent in stage 2. Slow wave sleep includes stages 3 and 4. REM sleep constitutes about 30% of the sleep time and lasts for 5–30 minutes in each cycle of sleep.
Types of sleep disorders and their treatment are given in Table 5.1 .
| Sleep disorder | Treatment |
|---|---|
| Sedatives and hypnotics |
| Amphetamine, modafinil, amitriptyline |
| Tricyclic antidepressants |
Classification of sedatives and hypnotics
- 1.
Benzodiazepines (BZDs) *
* Mnemonic to recollect BZDs: Sleep aids – D e L ux C 3 OT, MAT, FaN.
: Diazepam, lorazepam, clonazepam, clobazam, chlordiazepoxide, oxazepam, temazepam, midazolam, alprazolam, triazolam, flurazepam, nitrazepam. - 2.
Barbiturates:
Long acting : Phenobarbitone
Short acting : Pentobarbitone
Ultrashort acting : Thiopentone, methohexitone
- 3.
Nonbenzodiazepine hypnotics: Zolpidem, zopiclone, zaleplon, eszopiclone
- 4.
Others: Melatonin, ramelteon suvorexant
Benzodiazepines PH1.19
All BZDs have a benzene ring fused to a seven-membered diazepine ring.
Sites of action
Midbrain (ascending reticular formation), limbic system, brain stem, etc.
Mechanism of action
BZDs facilitate action of GABA – they potentiate inhibitory effects of GABA.
BZDs have no GABA-mimetic action.
Pharmacological actions and therapeutic uses
- 1.
Sedation and hypnosis: BZDs decrease time required to fall asleep (sleep latency). The total sleep time is increased. They shorten all stages of NREM sleep except stage 2, which is prolonged. The duration of REM sleep is usually decreased. BZDs reduce night awakenings and produce refreshing sleep.
At present, BZDs are preferred to barbiturates for treatment of short-term insomnia because:
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They have a wide therapeutic index.
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They cause near-normal sleep; less rebound phenomena on withdrawal.
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They produce minimal hangover effects (headache and residual drowsiness on waking).
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They cause minimal respiratory depression.
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They are less likely to cause tolerance and dependence when used for short period.
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They have no enzyme-inducing property; hence, drug interactions are less.
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They have a specific BZD-receptor antagonist, flumazenil, for the treatment of overdosage.
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Long-term use of BZDs for insomnia is not recommended because of development of tolerance, dependence and hangover effects; but these drugs are ideal for occasional use by air travellers, shift workers, etc.
- 2.
Anticonvulsant: Diazepam, lorazepam, clonazepam, clobazam, etc. have anticonvulsant effect. Intravenous (i.v.) diazepam/lorazepam is used to control life-threatening seizures in status epilepticus, tetanus, drug-induced convulsions, febrile convulsions, etc. Clonazepam is used in the treatment of absence seizures.
- 3.
Diagnostic (endoscopies) and minor operative procedures: i.v. BZDs are used because of their sedative–amnesic–analgesic and muscle relaxant properties.
- 4.
Preanaesthetic medication and general anaesthesia (GA): These drugs are used as preanaesthetic medication because of their sedative–amnesic and anxiolytic effects. Hence, the patient cannot recall the perioperative events later. i.v. diazepam, lorazepam, midazolam, etc. are combined with other CNS depressants to produce GA.
- 5.
Antianxiety (anxiolytic) effect: Some of the BZDs (diazepam, oxazepam, alprazolam, lorazepam, chlordiazepoxide, etc.) have selective antianxiety action at low doses. The anxiolytic effect is due to their action on limbic system. Tolerance to antianxiety action of BZDs develops only on prolonged use.
- 6.
Muscle relaxant (centrally acting): They reduce skeletal muscle tone by inhibiting polysynaptic reflexes in the spinal cord. The relaxant effect of BZDs is useful in spinal injuries, tetanus, cerebral palsy and to reduce spasm due to joint injury or sprain.
- 7.
To treat alcohol-withdrawal symptoms: Long-acting BZDs, such as chlordiazepoxide and diazepam are used.
- 8.
Conscious sedation: See p. 181.
The above-mentioned uses/actions can be summarized as follows:
Pharmacokinetics
BZDs are usually given orally or intravenously and occasionally by rectal route (diazepam) in children. The rate of absorption following oral administration is variable; absorption is erratic from intramuscular (i.m.) site of administration; hence rarely used. They have a large volume of distribution. They have a short duration of action on occasional use because of rapid redistribution, hence, are free of residual (hangover) effects, even though elimination half-life is long. BZDs are metabolized in liver. Some undergo enterohepatic recycling. Some of them produce active metabolites which have long half-life; hence, cumulative effects may be seen. Oxazepam is not significantly metabolized in liver. The metabolites are excreted in urine. BZDs cross placental barrier.
Adverse effects
BZDs have a wide margin of safety. They are generally well tolerated. The common side effects are drowsiness, confusion, blurred vision, amnesia, disorientation, tolerance and drug dependence. Withdrawal after chronic use causes symptoms like tremor, insomnia, restlessness, nervousness and loss of appetite. Use of BZDs during labour may cause respiratory depression and hypotonia in newborn (Floppy baby syndrome). In some patients, these drugs may produce paradoxical effects, i.e. convulsions and anxiety.
Important features of BZDs are given in Table 5.2 .
| Drug | Formulations with oral dose | Important points |
|---|---|---|
| Diazepam (prototype drug) | Oral, i.v., i.m., rectal, 5–10 mg |
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| Flurazepam | Oral, 15 mg |
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| Nitrazepam | Oral, 5–10 mg |
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| Oxazepam | Oral, 15 mg |
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| Lorazepam | Oral, i.m., i.v., 0.5–2 mg |
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| Alprazolam | Oral, 0.5–2 mg |
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| Temazepam | Oral, 7.5–30 mg |
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| Triazolam | Oral, 0.125–0.25 mg |
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| Midazolam | i.v., i.m., 1–2.5 mg (i.v.) |
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| Chlordiazepoxide | Oral, i.m., i.v., 50–100 mg |
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Inverse agonist (β-carboline).
Its interaction with BZD receptors will produce anxiety and convulsions.
Benzodiazepine antagonist (flumazenil).
Flumazenil competitively reverses the effects of both BZD agonists (CNS depression) and BZD inverse agonists (CNS stimulation, Fig. 5.4 ). Flumazenil is not used orally because of its high first-pass metabolism. It is given by i.v. route and has a rapid onset of action. Flumazenil is used in the treatment of BZD overdosage and to reverse the sedative effect of BZDs during GA. It can also be used to reverse the hypnotic effect of zolpidem, zaleplon and eszopiclone. Adverse effects include confusion, dizziness and nausea. It may precipitate withdrawal symptoms (anxiety and convulsions) in dependent subjects.
Barbiturates PH1.19
All barbiturates are derivatives of barbituric acid. They are nonselective CNS depressants and act at many sites, ascending reticular activating system (ARAS) being the main site.
Mechanism of action
Barbiturates have GABA facilitatory action – they potentiate inhibitory effects of GABA.
At high concentrations, barbiturates have GABA-mimetic effect (i.e. barbiturates can directly increase Cl − conductance into the neuron).
Pharmacological actions and uses
- 1.
Sedation and hypnosis: Barbiturates were used in the treatment of insomnia. They decrease sleep latency, duration of REM sleep, stage 3 and 4 of NREM sleep. They cause marked alteration of sleep architecture. At present, barbiturates are not recommended because:
- ■
They have a low therapeutic index.
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They cause rebound increase in REM sleep on stoppage of therapy.
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They cause marked respiratory depression.
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They produce marked hangover effects (headache and drowsiness next day morning).
- ■
They cause high degree of tolerance and drug dependence.
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They are potent enzyme inducers and cause many drug interactions.
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They have no specific antidote.
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- 2.
General anaesthesia (GA): Ultrashort-acting barbiturates (thiopentone and methohexitone) may be used for induction of GA.
- 3.
Anticonvulsant: Phenobarbitone has anticonvulsant effect and is used in the treatment of status epilepticus and generalized tonic–clonic seizures (GTCS, grand mal epilepsy).
- 4.
Neonatal jaundice of nonhaemolytic type: Phenobarbitone may be used to reduce serum bilirubin levels. It induces glucuronyl transferase enzyme and hastens the metabolism of bilirubin.
Adverse effects
- 1.
The common side effects are drowsiness, confusion, headache, ataxia, hypotension and respiratory depression.
- 2.
Hypersensitivity reactions like skin rashes, itching and swelling of face may occur.
- 3.
Tolerance develops to their sedative and hypnotic actions on repeated use.
- 4.
Physical and psychological dependence develops on repeated use.
- 5.
Prolonged use of phenobarbitone may cause megaloblastic anaemia by interfering with absorption of folic acid from gut.
- 6.
They may precipitate attacks of acute intermittent porphyria by inducing ALA synthase that catalyses the production of porphyrins; hence, barbiturates are contraindicated in porphyria.
- 7.
Acute barbiturate poisoning: The signs and symptoms are drowsiness, restlessness, hallucinations, hypotension, respiratory depression, convulsions, coma and death.
Treatment of acute barbiturate poisoning
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Maintain airway, breathing and circulation.
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Maintain electrolyte balance.
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Gastric lavage – after stomach wash, administer activated charcoal that may enhance the elimination of phenobarbitone. Endotracheal intubation is performed before gastric lavage to protect the airway in unconscious patients.
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Alkaline diuresis – there is no specific antidote for barbiturates; main treatment is alkaline diuresis. i.v. NaHCO 3 alkalinizes urine. Barbiturates are weakly acidic drugs. In alkaline urine, barbiturates exist in ionized form, so they are not reabsorbed while passing through renal tubules and are rapidly excreted in urine.
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Haemodialysis is employed in severe cases.
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Drug interactions
Barbiturates are potent inducers of hepatic microsomal enzymes and reduce the effectiveness of co-administered drugs (e.g. oral contraceptives [OCs], oral anticoagulants and oral hypoglycaemics).
Nonbenzodiazepine hypnotics PH1.19
They include zolpidem, zopiclone, zaleplon, eszopiclone and etizolam. They have less potential for abuse than BZDs.
They have less antianxiety, anticonvulsant and muscle relaxant effects than BZDs. Effect on REM sleep is less as compared to BZDs.
Zolpidem
Zolpidem mainly produces hypnotic effect – decreases sleep latency and increases duration of sleep time in insomnia. It produces near-normal sleep like BZDs with minimal alteration in REM sleep; causes minimal hangover effects and rebound insomnia; less likely to produce tolerance and drug dependence; lacks anticonvulsant, antianxiety and muscle relaxant effects. It is given orally, well absorbed, metabolized in liver and excreted in urine. It has a short duration of action and is used for short-term treatment of insomnia. The actions of zolpidem are antagonized by flumazenil. The common side effects are headache, confusion, nausea and vomiting.
Mechanism of action
Zopiclone
It is orally effective and is used for short-term treatment of insomnia. It produces near-normal sleep like BZDs. The side effects are headache, drowsiness, GI disturbances and metallic taste.
Zaleplon
It is useful in sleep onset insomnia. It is the shortest acting non-BZD hypnotic.
Eszopiclone
It is used orally for short- and long-term treatment of insomnia.
Etizolam
It is a BZD analogue with hypnotic, anticonvulsant, muscle relaxant and antianxiety effects. It is useful for short-term treatment of insomnia.
Melatonin
It is the hormone secreted by the pineal gland; involved in the maintenance of sleep–wake cycle and circadian rhythm.
Ramelteon
It is a melatonin-receptor (MT 1 and MT 2 ) agonist, can be used orally for the treatment of sleep onset insomnia. It reduces sleep latency and prolongs total duration of sleep. There is no rebound insomnia on withdrawal; does not cause tolerance on chronic use. The important adverse effects are fatigue and dizziness.
Tasimelteon
It is another melatonin-receptor agonist used for the treatment of circadian rhythm disorder in blind patients.
Suvorexant
It prevents orexin from maintaining wakefulness by blocking orexin receptors. It is useful in chronic insomnia.
General anaesthetics PH1.18
GA refers to drug-induced reversible loss of consciousness and all sensations. The features of GA are as follows:
- 1.
Reversible loss of consciousness.
- 2.
Reversible loss of sensation.
- 3.
Analgesia and amnesia.
- 4.
Muscle relaxation and abolition of reflexes.
There is no single anaesthetic agent that can produce all the above effects. Hence, anaesthetic protocol includes:
- 1.
Premedication.
- 2.
Induction of anaesthesia (e.g. propofol).
- 3.
Maintenance of anaesthesia (e.g. N 2 O + isoflurane).
- 4.
Skeletal muscle relaxation.
- 5.
Analgesia – as premedication, during and after the operation.
- 6.
Use of other drugs:
- ■
To reverse neuromuscular blockade.
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To reverse the residual effects of opioids (naloxone) and BZDs (flumazenil).
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Minimal alveolar concentration (MAC) is the minimum concentration of an anaesthetic in alveoli required to produce immobility in response to a painful stimulus in 50% patients. It indicates the potency of inhalational general anaesthetics (N 2 O > 100%, halothane 0.75%).
Mechanism of action of general anaesthetics
The main site of action of anaesthetics is reticular formation, which normally maintains a state of consciousness. Most anaesthetics decrease transmission in reticular formation by enhancing the activity of inhibitory transmitters like GABA (e.g. BZDs, barbiturates and propofol) and blocking the activity of excitatory transmitters (e.g. blockade of N-methyl-D-aspartate [NMDA] glutamate receptors by ketamine and nitrous oxide).
Stages of GA ( Table 5.3 ): Stages I–IV are seen mainly with ether because of its slow action. Stage II is the most dangerous period. Surgical procedures are performed in stage III. The aim of induction is to reach stage III as early as possible followed by maintenance anaesthesia and muscle relaxation.
| I. Stage of analgesia | II. Stage of excitement | III. Stage of surgical anaesthesia | IV. Stage of medullary paralysis |
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Classification
Inhalational anaesthetics
These are discussed under the following headings ( Tables 5.4 and 5.5 ).
- 1.
Gas/volatile liquid
- 2.
Noninflammable/inflammable
- 3.
Margin of safety
- 4.
Induction and recovery
- 5.
Skeletal muscle relaxation
- 6.
Analgesia
- 7.
Sensitization of myocardium
- 8.
Hepatotoxicity
- 9.
Irritation of respiratory passages
- 10.
Postoperative nausea and vomiting
- 11.
Other points
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Use of ether is obsolete.
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Halothane sensitizes the myocardium to the arrhythmogenic effect of catecholamines.
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Speed of induction and recovery depends on solubility of anaesthetic agent in blood and fat.
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Anaesthetics with low blood solubility produce rapid induction and recovery (e.g. N 2 O and desflurane).
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Anaesthetics with high solubility in blood produce slow induction and recovery (e.g. ether).
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Desflurane, isoflurane and ether irritate respiratory passages and can induce cough.
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The basis for combining halothane/isoflurane and nitrous oxide:
- (a)
The concentration (MAC) of halothane/isoflurane required to produce anaesthesia is reduced when given with N 2 O because of second gas effect. As the concentration of halothane/isoflurane required is reduced, the side effects of halothane/isoflurane (hypotension and respiratory depression) are reduced.
Second gas effect: N 2 O rapidly diffuses, whereas halothane/isoflurane diffuses poorly into the blood (alveoli ↔blood ↔brain). When these (halothane/isoflurane and N 2 O) anaesthetics are administered simultaneously, halothane/isoflurane also enters the blood rapidly along with rapidly diffusible gas (N 2 O). This is known as ‘second gas effect’.
- (b)
Because of reduction in the dosage, recovery will be faster.
- (c)
Halothane/isoflurane is a potent anaesthetic and poor analgesic, whereas N 2 O is a good analgesic and poor anaesthetic; hence, the combined effect of these two drugs results in potent anaesthesia and good analgesia.
- (a)
| Ether | Halothane | Nitrous oxide |
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| Halothane | Isoflurane | Desflurane | Sevoflurane |
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| Not pungent, well tolerated – preferred for induction and maintenance in children |
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Diffusion hypoxia.
Nitrous oxide has low blood solubility – when the administration of N 2 O is discontinued, it rapidly diffuses from the blood into alveoli and causes marked reduction of PaO 2 in the alveoli resulting in hypoxia which is known as diffusion hypoxia. It can be avoided by giving 100% O 2 for a few minutes immediately after N 2 O is discontinued.
Comparative features of halogenated anaesthetics are given in Table 5.5 .
Parenteral general anaesthetics
Inducing drugs
Propofol.
It is available as 1% emulsion for i.v. administration. Propofol is a commonly used, popular, rapidly acting anaesthetic.
Propofol acts on GABA receptors to increase chloride conductance and hyperpolarization of neurons, thus produces CNS depression. It has a rapid onset and short duration of action; for long procedures – it can be given in repeated doses or as continuous i.v. infusion. It is highly bound to plasma protein; crosses placental barrier and can be used in pregnant woman. It is metabolized in liver and excreted rapidly in urine.
- 1.
Induction of anaesthesia and recovery are rapid. Residual symptoms are less.
- 2.
Most suitable for outpatient surgical procedures.
- 3.
No irritation of air passages; suitable for use in asthmatics.
- 4.
Has antiemetic effect; hence, postoperative nausea and vomiting are rare.
- 5.
Can be used for both induction and maintenance of anaesthesia.
- 6.
Frequently used to sedate patients in ICU (intensive care unit) who are intubated.
- 7.
It is used in status epilepticus when not controlled by other drugs.
- 8.
Causes respiratory depression and fall in BP.
- 9.
Pain on injection occurs – can be reduced with lignocaine.
- 10.
In high doses, can cause acidosis and rise in blood lipid levels.
Note: Propofol – P opular, R apid acting, preferred for OP surgical procedures, causes FOL (fall) in BP.
Thiopentone sodium ( fig. 5.5 ).
It is an ultra short-acting barbiturate. It is a commonly used i.v. anaesthetic for induction of anaesthesia. It is highly lipid soluble, hence has a rapid onset and short duration (5–8 minutes) of action. It is highly alkaline (pH 10.5–11), hence highly irritant. It should be prepared as a fresh solution before injection. It is injected as 2.5% solution.
After a single i.v. dose, it rapidly enters highly perfused organs like brain, liver and heart, and produces anaesthesia. As blood level of the drug falls rapidly, it diffuses out of the central nervous system into the blood and then to less perfused organs like skeletal muscle and adipose tissue. This redistribution results in termination of drug action. Repeated doses will result in accumulation and delayed recovery.
Uses
- 1.
Thiopentone sodium is used for induction of anaesthesia.
- 2.
It is occasionally used as anticonvulsant in cases not controlled by other drugs.
- 3.
In subanaesthetic doses, thiopentone can be used for narcoanalysis in psychiatry.
Advantages of thiopentone
- 1.
Rapid induction of anaesthesia and rapid recovery.
- 2.
Does not sensitize the myocardium to circulating catecholamines.
Disadvantages/adverse effects of thiopentone
- 1.
Depresses the respiratory centre.
- 2.
Depresses the vasomotor centre and myocardium.
- 3.
Poor analgesic.
- 4.
Poor muscle relaxant.
- 5.
Causes laryngospasm.
- 6.
Accidental intra-arterial injection causes vasospasm and gangrene of the arm.
- 7.
It can precipitate acute intermittent porphyria by inducing the synthesis of ALA synthase, hence contraindicated in susceptible individuals (absolute contraindication).
Etomidate.
It is an i.v. anaesthetic used for induction – has a rapid onset and short duration of action. It causes minimal cardiovascular and respiratory depression.
Disadvantages/adverse effects
- 1.
Has poor analgesic effect.
- 2.
High incidence of pain on injection, postoperative nausea and vomiting.
- 3.
Restlessness and rigidity are common.
Slow-acting drugs
Ketamine.
It produces ‘dissociative anaesthesia’, which is characterized by sedation, amnesia, marked analgesia, unresponsiveness to commands and dissociation from the surroundings. It acts by blocking NMDA type of glutamate receptors. It is commonly given by i.v. route; other routes are i.m., oral and rectal. Ketamine has good analgesic effect . It causes bronchodilatation , suitable for use in asthmatics. Ketamine causes sympathetic stimulation – heart rate, BP, cardiac output and skeletal muscle tone are usually increased. It is used in patients with hypovolaemia . It is well tolerated by children .
Site of action: cortex and subcortical areas.
Ketamine is highly lipid soluble, rapidly enters highly perfused organs like brain, liver and heart; later, it redistributes to less perfused organs. It is metabolized in liver; excreted in urine and bile.
Uses
- 1.
For operations on the head, neck and face.
- 2.
For dressing burn wounds.
- 3.
Well suited for children/asthmatics undergoing short procedures.
Adverse effects and contraindications
- 1.
Increases BP and heart rate, hence is contraindicated in patients with hypertension and ischaemic heart disease.
- 2.
Increases intracranial pressure.
- 3.
Causes emergence delirium and hallucinations.
Benzodiazepines.
BZDs are slow-acting parenteral anaesthetics. They include diazepam, lorazepam and midazolam. Use of large doses delays recovery and prolongs amnesia. They have poor analgesic effect. They do not cause postoperative nausea and vomiting. The effects of BZDs can be reversed by flumazenil. They are useful for angiography, endoscopies, fracture reduction, etc.
Opioid analgesics.
They include fentanyl, alfentanil, sufentanil and remifentanil. They are potent analgesics and can be used along with anaesthetics – to decrease the requirement of anaesthetic. Alfentanil, sufentanil and remifentanil are shorter acting than fentanyl.
Dexmedetomidine
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Central α 2 -agonist → Sedation and analgesia.
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Causes minimal respiratory depression.
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Used intravenously to sedate critically ill patients.
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Common adverse effects are hypotension and bradycardia due to decreased central sympathetic outflow.
Complications of general anaesthesia
CVS: Hypotension, cardiac arrhythmias, cardiac arrest
Respiratory depression, aspiration pneumonia, apnoea
CNS: Convulsions, persistent sedation
GIT: Nausea, vomiting, hepatotoxicity
Nephrotoxicity
Malignant hyperthermia
Preanaesthetic medication PH1.18
It is the use of drugs before administration of anaesthetics to make anaesthesia more pleasant and safe.
Objectives/aims of premedication
- 1.
To reduce anxiety and apprehension: BZDs like diazepam, lorazepam or midazolam are preferred because of their sedative, amnesic, calming, anxiolytic effects and wide margin of safety. They reduce anxiety by acting on limbic system.
- 2.
To prevent vagal bradycardia and to reduce salivary secretion caused by anaesthetics: Antimuscarinic agents such as atropine or glycopyrrolate are used to prevent vagal bradycardia and hypotension. They also prevent laryngospasm by reducing respiratory secretion. Glycopyrrolate is preferred because it is potent, does not produce CNS effects and causes less tachycardia.
- 3.
To relieve pre- and postoperative pain: Opioid analgesics such as morphine, pethidine or fentanyl may be used to relieve pain. The limitations with opioids are respiratory depression, hypotension, nausea, vomiting, constipation, biliary spasm and bronchospasm in asthmatics. NSAIDs like diclofenac can also be used.
- 4.
For antiemetic effect: Metoclopramide, domperidone or ondansetron may be used to control vomiting. Acute dystonias and extrapyramidal symptoms (EPS) are the main side effects of metoclopramide; domperidone rarely produces EPS. 5-HT 3 antagonist like ondansetron is the preferred antiemetic as it rarely causes adverse effects and is well tolerated.
- 5.
To prevent acid secretion and stress ulcer: H 2 -blocker such as ranitidine or proton-pump inhibitor like omeprazole may be used to reduce gastric acid secretion and aspiration pneumonia especially before prolonged surgery.
- 6.
To hasten gastric emptying before emergency surgery: Metoclopramide or domperidone may be used. They are prokinetic drugs – increase the tone of lower oesophageal sphincter and accelerate gastric emptying, thus prevent aspiration pneumonia.
Conscious sedation
It is a level of CNS depression where a patient does not lose consciousness but is able to communicate and cooperate during the procedure/treatment. It is used in:
- 1.
Uncooperative patients.
- 2.
Anxious patients.
- 3.
Emotionally compromised patients.
It should be avoided in chronic obstructive pulmonary disease (COPD), pregnancy, prolonged surgery, psychoses, etc. The drugs used are BZDs such as diazepam (oral, i.v.), midazolam (i.v.) and temazepam (oral); nitrous oxide + oxygen (inhalation); propofol (i.v. infusion) and fentanyl (i.v.).
Local anaesthetics PH1.17
Local anaesthetics (LAs) are drugs which, when applied topically or injected locally, block nerve conduction and cause reversible loss of all sensation in the part supplied by the nerve. The order of blockade of nerve function proceeds in the following manner – pain, temperature, touch, pressure and finally skeletal muscle power.
Chemistry ( fig. 5.6 )
LAs are weak bases. They consist of three parts: (i) hydrophilic amino group; (ii) lipophilic aromatic group; and (iii) intermediate ester or amide linkage.
Classification of local anaesthetics
- 1.
According to clinical use
- (a)
Surface anaesthetics: Cocaine, lignocaine, tetracaine, benzocaine, oxethazaine, proparacaine, butylaminobenzoate.
- (b)
Injectable anaesthetics
- (i)
Short acting with low potency: Procaine, chloroprocaine.
- (ii)
Intermediate acting with intermediate potency: Lignocaine, mepivacaine, prilocaine, articaine.
- (iii)
Long acting with high potency: Tetracaine, bupivacaine, dibucaine, ropivacaine.
- (i)
- (a)
- 2.
According to structure
- (a)
Esters *
* Note: Esters have one ‘i’; amides have two ‘i’ (i, i).
: Coca i ne, proca i ne, chloroproca i ne, benzoca i ne, tetraca i ne. - (b)
Amides * : L i gnoca i ne, mep i vaca i ne, bup i vaca i ne, pr i loca i ne, art i ca i ne, rop i vaca i ne.
- (a)
Mechanism of action
LAs act on voltage-sensitive Na + channels. Sodium channels exist in resting, open and inactivated states (resting → open → inactivated state). The channels have to recover from the inactivated state to resting state before they can be opened in response to an impulse.
The LAs in ‘unionized’ form easily penetrate nerve sheath and axon membrane. Within the axoplasm, the molecules become ‘ionized’ and block the voltage-gated Na + channels.
- ■
Blockade is frequency dependent.
- ■
Action of LA is pH dependent and the penetrability of LA is increased at alkaline pH (i.e. when the unionized form is more). Penetrability is very poor at acidic pH of tissues. In infected tissues, there is a low pH, which causes ionization of the drug. This reduces penetration of LA through the cell membrane, thus decreases the effectiveness of LAs. Therefore, LAs are less effective in inflamed and infected areas .
- ■
Diameter of nerve fibres: LAs block small fibres first followed by larger fibres.
- ■
Myelinated fibres are blocked earlier than nonmyelinated nerves of the same diameter.
- ■
Sensory fibres are blocked earlier than motor fibres because of their high firing rate and longer duration of action potential.
- ■
Fibres in the centre are blocked later than the ones located in the circumference of the nerve bundle.
Factors affecting local anaesthetic action
- 1.
p K a : Higher the p K a , more is the ionized fraction of the drug at physiological pH. Hence, onset of action is slow and vice versa, e.g. the p K a of procaine is 9.1. So, it has slow onset of action; whereas p K a of lignocaine is 7.7 – it has rapid onset of action. Although p K a of chloroprocaine is 9.1, it has a rapid onset of action.
- 2.
Degree of plasma protein binding: Higher the plasma protein binding, longer the duration of action of the drug, e.g. procaine is poorly bound to plasma proteins, hence has a short duration of action, whereas bupivacaine is highly plasma protein bound and has longer duration of action.
- 3.
Rate of diffusion from the site of administration: It depends on the initial concentration gradient of the drug. Higher the concentration, rapid is the onset of action.
- 4.
Lipid solubility: Higher the lipid solubility, more is the potency of the drug, e.g. lignocaine is more potent than procaine as it is more lipid soluble.
- 5.
Presence of vasoconstrictor: Prolongs the duration of action of LAs. The commonly used vasoconstrictor with LAs is adrenaline.
Combination of vasoconstrictor with local anaesthetic
Addition of a vasoconstrictor (e.g. adrenaline) to the LA has the following advantages:
- 1.
Slow absorption from the local site which results in prolonged duration of action of LAs.
- 2.
Decreased bleeding in the surgical field.
- 3.
Slow absorption of LA reduces its systemic toxicity.
Disadvantages and contraindications of combining vasoconstrictor with LA:
- 1.
Intense vasospasm and ischaemia in tissues with end arteries may cause gangrene of the part (e.g. fingers, toes, penis, ear lobule and tip of the nose). Hence, use of vasoconstrictors is contraindicated in these sites.
- 2.
Absorption of adrenaline can cause systemic toxicity – tachycardia, palpitation, rise of BP and precipitation of angina or cardiac arrhythmias. Hence, combined preparation (LA with adrenaline) should be avoided in patients with hypertension, congestive cardiac failure (CCF), arrhythmias, ischaemic heart disease and uncontrolled hyperthyroidism.
- 3.
May delay wound healing by reducing the blood flow to the affected area.
Pharmacological actions
- 1.
Nervous system
- (a)
Peripheral nerves: Autonomic fibres are blocked earlier than somatic fibres. Sensation of pain disappears first followed by temperature, touch, pressure and motor functions.
- (b)
CNS : Most of the LAs cross the blood–brain barrier (BBB) – initially they cause CNS stimulation and then depression in higher doses. They cause excitement, tremor, twitching, restlessness and convulsions. Large doses can cause respiratory depression, coma and death.
- (a)
- 2.
Cardiovascular system
- (a)
Heart: LAs, by blocking Na + channels, decrease abnormal pacemaker activity, contractility, conductivity, excitability, heart rate, cardiac output and increase effective refractory period.
- (i)
At higher concentrations, i.v. administration of LAs may precipitate cardiac arrhythmias.
- (ii)
Bupivacaine is more cardiotoxic than other LAs – may cause cardiovascular collapse and death.
- (iii)
Lignocaine decreases automaticity and is useful in ventricular arrhythmias.
- (i)
- (b)
Blood vessels: LAs produce hypotension due to vasodilatation and myocardial depression.
- (a)
Pharmacokinetics
Most of the ester-linked LAs are rapidly metabolized by plasma cholinesterase, whereas amide-linked drugs are metabolized mainly in liver. LAs (procaine, lignocaine, etc.) are not effective orally because of high first-pass metabolism. In liver diseases, the metabolism of lignocaine may be impaired; hence, dose must be reduced accordingly.
Comparative features of esters and amides are shown in Table 5.6 .
| Procaine | Lignocaine |
| Ester type of LA | Amide type of LA |
| Short acting | Intermediate acting |
| Has poor tissue penetrability, hence no surface anaesthetic effect | Has good tissue penetrability |
| Has slow onset of action | Has rapid onset of action |
| Is metabolized by plasma cholinesterase | Is metabolized by hepatic microsomal enzymes |
| Allergic reactions are common with esters | Allergic reactions are rare |
| Useful for infiltration and nerve block anaesthesia; at present, it is rarely used | Widely used for all types of anaesthesia – spinal, epidural, i.v. regional block, nerve block, infiltration and surface anaesthesia |
Adverse effects
- 1.
CNS: LAs initially cause CNS stimulation followed by depression. They are restlessness, tremor, headache, drowsiness, confusion, convulsions followed by respiratory depression, coma and death.
- 2.
CVS: Bradycardia, hypotension, cardiac arrhythmias and rarely cardiovascular collapse and death. Bupivacaine is highly cardiotoxic.
- 3.
Allergic reactions: These are skin rashes, itching, erythema, urticaria, wheezing, bronchospasm and rarely anaphylactic reaction. The incidence of allergic reactions is more with ester-linked LAs than with amide-linked LAs.
- 4.
Mucosal irritation (cocaine) and methaemoglobinaemia (prilocaine) may be seen.
- 5.
Methylparaben, preservative in LA preparation, may cause allergic reaction.
Important properties of LAs are given in Table 5.7 .
Table 5.7 ■Properties of local anaestheticsDrug Group Duration of action (minutes) Potency Onset Tissue penetrability Other points Procaine Ester 15–30 (short) Low Slow Poor No surface anaesthesia
Chloroprocaine Ester 15–30 (short) Low Rapid – –
Tetracaine Ester 120–240 (long) High Very slow Moderate - •
Widely used in spinal and corneal anaesthesia
- •
High systemic toxicity because of slow metabolism
Cocaine Ester – – Intermediate Good - •
Inhibits the reuptake of NA in both central and peripheral nerves
- •
Causes tachycardia, rise in BP, mydriasis and euphoria
- •
Rarely used
Lignocaine Amide 30–60 (intermediate) Intermediate Rapid Good Most widely used local anaesthetic; also used in ventricular arrhythmias
Mepivacaine Amide 45–90 (intermediate) Intermediate Intermediate – No surface anaesthesia
Bupivacaine Amide 120–240 (long) High Intermediate Moderate Highly cardiotoxic, widely used for spinal, epidural, infiltration and nerve block – because of long duration of action; low concentration used for epidural analgesia during labour
Ropivacaine Amide 120–360 (long) Intermediate Intermediate Moderate Similar to bupivacaine, less cardiotoxic
Prilocaine Amide Intermediate – Intermediate Moderate Widely used; can cause methaemoglobinaemia
Dibucaine Amide 180-600 (long) High Slow Good Useful as topical anaesthetic for anal mucous membrane
Articaine Amide 60 – Rapid – Used for infiltration and nerve block anaesthesia; can cause methaemoglobinaemia, paraesthesia and neuropathy
Note: NA, noradrenaline.
- 6.
Adverse effects due to the use of vasoconstrictor (see p. 183)
Procaine (see table 5.6 ).
It is a prototype drug for esters. It is rarely used now because of availability of better agents.
Cocaine.
It is an alkaloid; excellent surface anaesthetic but rarely used because of its addiction liability.
Chloroprocaine has a p K a of 9.1, but has rapid onset of action.
Tetracaine.
An ester type of LA, it has long duration but slow onset of action. It is useful for spinal anaesthesia because of its long duration of action. It is mainly used as a surface anaesthetic for eye, nose and upper respiratory tract.
Lignocaine.
It is a prototype agent for amides. It is a very popular anaesthetic used widely for topical application, infiltration, spinal and conduction block anaesthesia. It is also available as a patch – can be used to control severe pain of postherpetic neuralgias.
Bupivacaine.
It is a widely used LA. It is potent and has a long duration of action. It produces more sensory than motor blockade, hence very popular for obstetric analgesia. It is highly cardiotoxic and may precipitate ventricular arrhythmias.
Levobupivacaine: It is similar to bupivacaine; but less cardiotoxic and less likely to cause seizures.
Ropivacaine.
It is less potent and less cardiotoxic than bupivacaine. Its duration of action is similar to bupivacaine. It is used for both epidural and regional anaesthesia. It is more selective for sensory fibres than motor fibres, hence used in obstetric analgesia.
Prilocaine.
It is an amide type of LA. It has intermediate onset and duration of action. It has poor vasodilatory effect, hence can be used without a vasoconstrictor. Prilocaine is not suitable for labour pain because of the risk of neonatal methaemoglobinaemia. It is mainly used for infiltration and i.v. regional anaesthesia.
Eutectic mixture (EMLA – eutectic mixture of local anaesthetics – lignocaine [2.5%] and prilocaine [2.5%]).
The melting point of the mixture is less than that of either compound alone. It can anaesthetize intact skin. EMLA has to be applied 1 hour before the procedure and is used for dermal anaesthesia during venesection and skin graft procedures. It should not be used on mucous membranes or abraded skin. It is contraindicated in patients with methaemoglobinaemia and infants.
Dibucaine.
It is a very potent, highly toxic and the longest acting LA. It is rarely used for spinal anaesthesia, and is also available for topical application on mucous membrane and skin.
Benoxinate.
It is a surface anaesthetic; useful for corneal anaesthesia.
Benzocaine and butylaminobenzoate.
Surface anaesthetics; cause minimal systemic toxicity; available as ointment and lozenges; used for haemorrhoids, anal fissure and sore throat.
Oxethazaine.
It is a topical anaesthetic and is used to anaesthetize gastric mucosa . It produces symptomatic relief in gastritis. It is available in combination with antacids.
Techniques of local anaesthesia ( table 5.8 )
Surface anaesthesia (topical anaesthesia)
LA is applied on the abraded skin and mucous membrane of the nose, mouth, eyes, throat, upper respiratory tract, oesophagus, urethra, ulcers, burns, fissures, etc. Motor function is intact. Tetracaine 2%, lignocaine 2%–10%, benzocaine 1%–2%, etc. are used for topical application. Surface anaesthetics are available as solution, ointment, gel, jelly, cream, spray, lozenges, etc.
| LA technique | Drugs | Therapeutic application (uses) |
|---|---|---|
| Surface anaesthesia (topical) |
| Anaesthetize mucous membrane of the eyes, nose, mouth, cornea, urinary and upper respiratory tracts, fissures, ulcers, etc. |
| Infiltration anaesthesia |
|
|
| Nerve block anaesthesia | Most of the anaesthetics | Used for surgery and neuralgias |
| Spinal anaesthesia |
| Surgery on lower limbs, lower abdomen, perineum, etc., caesarean section |
| Epidural anaesthesia |
| Obstetric analgesia |
| i.v. regional anaesthesia (Bier’s block) |
| For upper and lower limb surgeries |
| To anaesthetize gastric mucosa |
| Peptic ulcer |
Addition of adrenaline does not prolong the duration of surface anaesthesia because of poor penetration. Topical anaesthetics are useful in many diagnostic procedures like tonometry in eye and during endoscopies.
EMLA is used to anaesthetize the intact skin and structures in the superficial subcutaneous tissues.
Infiltration anaesthesia
LA is injected directly into tissues to be operated; it blocks sensory nerve endings. The most frequently used LAs for infiltration are lignocaine (0.5%–1%), procaine (0.5%–1%) and bupivacaine (0.125%–0.25%). Addition of adrenaline to LA (1:50,000–250,000) prolongs the duration of anaesthesia.
Infiltration anaesthesia is suitable only for small areas. The main disadvantage of infiltration anaesthesia is the requirement of large amounts of the drug to anaesthetize relatively small area. It can be used for drainage of an abscess, excision of small swelling, suturing of cut wounds, episiotomy, etc. Infiltration anaesthesia is contraindicated, if there is local infection and clotting disorders.
Conduction block
(I) Field block anaesthesia.
It is achieved by injecting an LA subcutaneously, which anaesthetizes the area distal to the injection. This principle is used in case of minor procedures of scalp, anterior abdominal wall, upper and lower extremities in which a smaller dose produces larger area of anaesthesia.
(II) Nerve block anaesthesia.
LA is injected very close to or around the peripheral nerve or nerve plexuses. It produces larger areas of anaesthesia than field block.
- 1.
Brachial plexus block for procedures on upper limb.
- 2.
Cervical plexus block for surgery of the neck.
- 3.
Intercostal nerve block for anterior abdominal wall surgery.
- 4.
Sciatic and femoral nerve block for surgery distal to the knee.
In this procedure, the requirement of LA is less than that of field block and infiltration anaesthesia.
Spinal anaesthesia
It is one of the most popular forms of anaesthesia. LA is injected into the subarachnoid space to anaesthetize spinal roots.
Site of injection.
The anaesthetic is injected into the space between L2 and L3 or L3 and L4 below the lower end of the spinal cord. The level of anaesthesia is influenced by (i) site of injection, (ii) amount of fluid injected, (iii) force of injection, (iv) specific gravity of the drug solution (hyperbaric [in 10% glucose], hypobaric [in distilled water] or isobaric) and (v) position of the patient – lying prone/lateral or tilted with head-down position.
LAs used for spinal anaesthesia.
They are lignocaine, tetracaine, bupivacaine, etc. Addition of adrenaline to spinal anaesthetic increases the duration or intensity of block.
Uses.
Spinal anaesthesia can be used for surgical procedures below the level of umbilicus, i.e. lower limb surgery, caesarean section, obstetric procedures, prostatectomy, surgery on perineum, appendicectomy, etc.
Advantages of spinal anaesthesia.
No loss of consciousness, good muscle relaxation and good analgesia. Patients with cardiac, pulmonary and renal disease tolerate spinal anaesthesia better than GA.
Complications
- 1.
Headache is due to leakage of CSF and can be reduced by using very fine needle.
- 2.
Hypotension is due to blockade of sympathetic vasoconstrictor fibres to blood vessels. Venous return to the heart is reduced due to paralysis of skeletal muscles in the legs. Hypotension is treated by raising foot end and administration of sympathomimetics such as ephedrine, mephentermine and phenylephrine.
- 3.
Respiratory paralysis: It is due to paralysis of intercostal muscles. Respiratory failure may occur due to respiratory centre ischaemia as a result of hypotension.
- 4.
Septic meningitis and nerve injury are extremely rare at present, because of good anaesthetic practice.
- 5.
Postoperative urinary retention may occur.
Contraindications.
Spinal anaesthesia should not be used in young children, vertebral abnormalities, sepsis in the region of lumbar puncture site, hypotension and shock.
Epidural anaesthesia
LA is injected into epidural space (thoracic or lumbar region or sacral canal) where it acts on spinal nerve roots. Lignocaine and bupivacaine are commonly used. It is safer, but the technique is more difficult than spinal anaesthesia. Epidural anaesthesia is slower in onset than spinal anaesthesia. It requires a much larger amount of the drug. Epidural analgesia is being used in obstetrics during labour. Low concentration of bupivacaine or ropivacaine is used to block pain sensation without significant motor block. Ropivacaine is less cardiotoxic and motor blockade is less than bupivacaine.
Intravenous regional anaesthesia (bier’s block)
It is mainly used in anaesthetizing the upper limb. Lignocaine and prilocaine are commonly used. LA is injected into vein of the limb in which the blood flow is occluded by a tourniquet.
Drug interactions
- 1.
Lignocaine × propranolol: Propranolol by reducing hepatic blood flow, impairs the clearance of lignocaine, which may result in toxicity.
- 2.
Procaine × sulphonamides: Procaine is hydrolysed to PABA – reduces the effect of sulphonamides.
Alcohols (ethanol and methanol) PH1.20
The actions of alcohol are depicted in Fig. 5.7 .
- ■
Ethyl alcohol follows zero-order kinetics of elimination.
- ■
In chronic alcoholics, increased amount of toxic metabolite of paracetamol is formed as a result of induction of its metabolizing enzyme, CYP2E1.
- ■
As alcohol is present in exhaled air, it can be detected by breath analyser.
Therapeutic uses of alcohol
- 1.
Antiseptic: 70% ethyl alcohol is used as an antiseptic on skin before giving injection and surgical procedure. Its antiseptic efficacy decreases above 90%. It should not be used on open wounds, mucosa, ulcers and on scrotum as it is highly irritant. It is not useful for disinfecting instruments as it promotes rusting.
- 2.
Trigeminal and other neuralgias: Injection of alcohol directly into nerve trunk relieves pain by destroying them.
- 3.
Prevent bedsores: Alcohol is used locally to prevent bedsores in bedridden patients.
- 4.
Methanol poisoning: Ethanol competes with methanol for metabolic enzymes and saturates them. Hence, it prevents the formation of toxic metabolites of methanol (formaldehyde and formic acid).
- 5.
Fever: Alcoholic sponges are useful to reduce body temperature.
Acute ethanol overdosage (acute alcohol intoxication).
The signs and symptoms of acute alcohol intoxication are drowsiness, nausea, vomiting, ataxia, hypotension, respiratory depression, hypoglycaemia, etc.
Treatment (note A–G).
It is a medical emergency. The main aim of therapy is to prevent severe respiratory depression and aspiration of vomitus.
- 1.
M aintain A irway, B reathing, C irculation, F luid and E lectrolyte balance, and G astric lavage if necessary.
- 2.
Intravenous glucose to correct hypoglycaemia.
- 3.
Thiamine is administered as i.v. infusion in glucose solution.
- 4.
Haemo D ialysis helps to hasten the recovery.
Withdrawal syndrome.
Sudden reduction/stoppage of alcohol in chronic alcoholics results in alcohol withdrawal syndrome. It manifests as restlessness, tremors, insomnia, nausea, vomiting, hallucinations, delirium, convulsions and collapse.
Treatment of alcohol withdrawal syndrome
- ■
BZDs (diazepam, chlordiazepoxide, etc.) are used to control anxiety, tremor, palpitation, sleep disturbances, confusion and convulsions associated with alcohol withdrawal.
- ■
Psychological support.
Treatment of chronic alcoholism PH1.23
- ■
Psychotherapy, occupational therapy and rehabilitation
- ■
Drug treatment of chronic alcoholism
- (a)
Disulfiram (alcohol aversion therapy): It causes aversion to alcohol.
Disulfiram inhibits aldehyde dehydrogenase and causes accumulation of acetaldehyde in blood and tissues (acetaldehyde syndrome). The signs and symptoms include nausea, vomiting, flushing, headache, sweating, tachycardia, palpitation, breathlessness, chest pain, hypotension, hypoglycaemia, confusion, shock and even death. This reaction is unpleasant; hence, person on disulfiram develops aversion to alcohol.
Drugs like metronidazole, griseofulvin and cefoperazone also have disulfiram-like action and produce similar reaction with alcohol. Doctors should warn the patient not to take alcohol and alcohol-containing products when they are on above-mentioned drugs.
- (b)
Naltrexone (opioid antagonist): It reduces alcohol craving and helps to maintain abstinence.
- (c)
Acamprosate: It activates GABA A receptors and reduces relapse.
- (d)
Ondansetron (5-HT 3 antagonist): It reduces alcohol consumption.
- (e)
Topiramate: It decreases craving for alcohol.
Methanol poisoning (methyl alcohol poisoning) PH1.21
This occurs when methylated spirit is consumed or when liquor is adulterated with methyl alcohol. Methanol is a mild CNS depressant. It is metabolized to formaldehyde and formic acid which, in turn, cause metabolic acidosis and injury to retina. The signs and symptoms of methanol poisoning are nausea, vomiting, abdominal pain, headache, vertigo, confusion, hypotension, convulsions and coma. Metabolic acidosis is due to formic acid which also causes dimness of vision, retinal damage and blindness.
Treatment
- 1.
Patient is kept in a dark room to protect the eyes from light.
- 2.
Maintain airway, breathing and circulation.
- 3.
Gastric lavage is done after endotracheal intubation.
- 4.
Intravenous sodium bicarbonate is given to correct acidosis and to prevent retinal damage.
- 5.
Ethanol (10%) is administered via nasogastric tube. Ethanol competes with methanol for metabolic enzymes and saturates them, thus prevents formation of toxic metabolites (formaldehyde and formic acid). Methanol is excreted unchanged in urine and breath.
- 6.
Fomepizole, an alcohol dehydrogenase inhibitor, is the preferred agent for the treatment of methanol poisoning. CNS depression is rare with fomepizole as compared to ethanol. It can also be used in ethylene glycol poisoning.
- 7.
Calcium leucovorin is administered intravenously (folate adjuvant therapy) to enhance metabolism of formate, thereby decreasing its levels.
- 8.
Haemodialysis is done to promote excretion of methanol and its toxic metabolites.
Antiepileptic drugs PH1.19
Epilepsy is a Greek word that means convulsions. Epilepsy is a disorder of brain function characterized by paroxysmal cerebral dysrhythmia. Major types of epilepsy are shown below.
Generalized seizures
- 1.
Generalized tonic–clonic seizures (GTCS, grand mal epilepsy): It is characterized by the following sequence of symptoms: Aura–epileptic cry–loss of consciousness–fall to the ground–tonic phase–clonic phase–period of relaxation–postepileptic automatism with confusional states.
- 2.
Absence seizures (petit mal epilepsy): It is characterized by sudden onset of staring, unresponsiveness with momentary loss of consciousness.
- 3.
Myoclonic seizures: It consists of single or multiple sudden, brief, shock-like contractions.
Partial seizures
- 1.
Simple partial seizures (SPS): The manifestations depend on the region of cortex involved. There may be convulsions (focal motor symptoms) or paraesthesia (sensory symptoms) without loss of consciousness.
- 2.
Complex partial seizures (CPS, temporal lobe epilepsy, psychomotor epilepsy): It is characterized by aura–amnesia–abnormal behaviour and automatism with impaired consciousness.
Chemical classification of antiepileptic drugs
- 1.
Hydantoins: Phenytoin, fosphenytoin.
- 2.
Barbiturate: Phenobarbitone.
- 3.
Iminostilbenes: Carbamazepine, oxcarbazepine.
- 4.
Carboxylic acid derivatives: Sodium valproate, divalproex.
- 5.
Succinimide: Ethosuximide.
- 6.
BZDs: Lorazepam, diazepam, clonazepam, clobazam.
- 7.
Others: Lamotrigine, topiramate, gabapentin, pregabalin, tiagabine, vigabatrin, zonisamide, levetiracetam, lacosamide.
Clinical classification of antiepileptic drugs
The classification of antiepileptic drugs is presented in Table 5.9 .
| Seizure type | Preferred drug | Alternative/adjunct drugs |
| Generalized tonic–clonic seizures (grand mal epilepsy) |
|
|
| Simple/complex partial seizures (SPS) |
|
|
| Absence seizures (petit mal epilepsy) |
|
|
| Myoclonic seizures |
|
|
| Status epilepticus |
|
|
Phenytoin (diphenylhydantoin)
Phenytoin is one of the most commonly used antiepileptic drugs. It has a selective antiepileptic effect and does not produce significant drowsiness.
Mechanism of action.
Phenytoin acts by stabilizing neuronal membrane ( Fig. 5.9 ) and prevents spread of seizure discharges. The sodium channels exist in three forms: resting, activated and inactivated states. Phenytoin delays recovery of Na + channels from inactivated state, thereby reduces neuronal excitability ( Fig. 5.9 ) and inhibits high-frequency firing.
At high concentrations, phenytoin inhibits Ca 2 + influx into neuron, reduces glutamate levels and increases responses to GABA.
Pharmacokinetics.
Phenytoin is absorbed slowly through the GI tract, widely distributed and highly (about 90%) bound to plasma proteins. It is almost completely metabolized in liver by hydroxylation and glucuronide conjugation. Repeated administration of phenytoin causes enzyme induction and increases the rate of metabolism of co-administered drugs. Phenytoin exhibits dose-dependent elimination, i.e. at low concentration (<10 mcg/mL), elimination occurs by first-order kinetics and plasma half-life is 10–24 hours; as the rate of administration increases, the metabolizing enzymes get saturated, kinetics changes to zero order, and plasma half-life increases to 60 hours; the plasma concentration increases markedly with slight increase in dose resulting in toxicity. Hence, therapeutic monitoring of phenytoin is essential for adjustment of dosage.
Uses.
Phenytoin is used for the treatment of:
- 1.
Generalized tonic–clonic seizures (grand mal epilepsy).
- 2.
Partial seizures.
- 3.
Trigeminal and other neuralgias.
- 4.
Status epilepticus: Phenytoin is administered intravenously in normal saline (it precipitates in glucose solution).
Adverse effects (note the ‘H’s).
Phenytoin has dose-dependent toxicity. The adverse effects are as follows:
- 1.
H ypertrophy and H yperplasia of gums (due to defect in collagen catabolism) – seen on chronic therapy and can be minimized by proper oral hygiene.
- 2.
H ypersensitivity reactions include skin rashes, neutropenia and rarely H epatic necrosis.
- 3.
H irsutism – due to increased androgen secretion.
- 4.
H yperglycaemia – due to decreased insulin release.
- 5.
Megaloblastic anaemia – due to folate deficiency.
- 6.
Osteomalacia – due to increased metabolism of vitamin D.
- 7.
H ypocalcaemia – due to decreased absorption of Ca 2+ from the gut.
- 8.
Fetal H ydantoin syndrome – cleft lip, cleft palate, digital H ypoplasia, etc. due to use of phenytoin during pregnancy.
At high concentration , phenytoin may cause the following side effects:
- 1.
CNS: Vestibulocerebellar syndrome – vertigo, ataxia, tremor, headache, nystagmus, psychological disturbances, etc. occur on chronic therapy.
- 2.
CVS: Hypotension and cardiac arrhythmias may occur on i.v. administration; extravasation of the drug causes local tissue necrosis.
- 3.
GIT: Nausea, vomiting and dyspepsia can be minimized by giving phenytoin after food.
Fosphenytoin
It is a prodrug of phenytoin, which is converted to phenytoin by phosphatases. Dose of fosphenytoin is expressed as phenytoin equivalents (PE). It is available for i.m. and i.v. administration. Fosphenytoin can be administered in normal saline or glucose. It has significantly less irritant effect on the veins than phenytoin. It is preferred to phenytoin in status epilepticus because of above advantages. The rate of i.v. infusion should not exceed 150 mg PE/minute. Hypotension and cardiac arrhythmias may occur with rapid administration.
Carbamazepine (iminostilbene)
Carbamazepine is chemically related to tricyclic antidepressants (TCAs).
Mechanism of action.
Like phenytoin, carbamazepine slows the rate of recovery of Na + channels from inactivation, thereby reduces neuronal excitability.
Pharmacokinetics.
Carbamazepine is absorbed slowly and erratically from GI tract, binds to plasma proteins, is well distributed in the body including the cerebrospinal fluid (CSF) and metabolized in liver. One of its metabolites retains anticonvulsant activity. Repeated use causes enzyme induction and reduces the effectiveness of the drug itself (autoinduction) as well as that of valproate, phenytoin, lamotrigine, topiramate, OC pills, etc.
Adverse effects.
The common adverse effects of carbamazepine include sedation, drowsiness, vertigo, ataxia, diplopia, blurred vision, nausea, vomiting and confusion. Hypersensitivity reactions are skin rashes, eosinophilia, lymphadenopathy and hepatitis. Rarely, it causes bone marrow depression with neutropenia, aplastic anaemia and agranulocytosis. On chronic therapy, it may cause water retention due to the release of antidiuretic hormone (ADH).
Uses
- 1.
Carbamazepine is one of the most commonly used antiepileptic drugs. It is the drug of choice in GTCS and partial (SPS and CPS) seizures.
- 2.
Carbamazepine is the drug of choice in the treatment of trigeminal neuralgias. It inhibits high-frequency discharges. The other drugs useful are phenytoin, gabapentin, TCAs (amitriptyline), etc. Other treatment options are surgical division, cryosurgery, injection of alcohol or phenol in close proximity to nerve or ganglia. It is not effective for diabetic neuropathy.
- 3.
It is used in the treatment of acute mania and bipolar disorder.
Oxcarbazepine (iminostilbene)
Oxcarbazepine is an analogue of carbamazepine. Mechanism of action and therapeutic uses are similar to carbamazepine. It is a prodrug and is converted to active form after administration. Its enzyme-inducing property is much less ; hence, drug interactions are few. It is less potent and less hepatotoxic than carbamazepine.
Eslicarbazepine
It is similar in structure to carbamazepine. It is useful for treatment of partial seizures.
Phenobarbitone (barbiturate)
Phenobarbitone is a barbiturate and was widely used as an antiepileptic drug. Its use has declined because of availability of safer drugs. It acts by potentiating GABA activity. Phenobarbitone is absorbed slowly but completely after oral administration; about 50% is bound to plasma proteins. Repeated administration causes enzyme induction and reduces the effectiveness of co-administered drugs.
Adverse effects.
The most common side effect of phenobarbitone is sedation, but tolerance develops gradually with continued administration. The other side effects are nystagmus, ataxia, confusion, megaloblastic anaemia and skin rashes. On chronic therapy, it may cause behavioural disturbances with impairment of memory in children (see Pharmacological actions of barbiturates on pp. 170–171).
Uses.
Phenobarbitone is effective in GTCS and partial seizures. It is the cheapest antiepileptic drug. It is also useful in the prophylactic treatment of febrile convulsions. In status epilepticus, phenobarbitone is injected intravenously when convulsions are not controlled with diazepam and phenytoin.
Ethosuximide (succinimide)
It is effective for the treatment of absence seizures. It acts by inhibiting T-type Ca 2+ current in thalamic neurons. It is completely absorbed after oral administration. The common side effects are GI disturbances like nausea, vomiting and anorexia. The other side effects are headache, hiccough, eosinophilia, neutropenia, thrombocytopenia with bone marrow depression and rarely skin rashes.
Valproic acid (sodium valproate): Carboxylic acid derivative
Sodium valproate is a broad-spectrum antiepileptic drug.
Mechanism of action
- 1.
Like phenytoin and carbamazepine, valproate delays the recovery of Na + channels from inactivation.
- 2.
Like ethosuximide, it blocks T-type Ca 2+ current in thalamic neurons.
- 3.
Increases the activity of GABA in the brain by:
- (a)
Increased synthesis of GABA by stimulating GAD (glutamic acid decarboxylase) enzyme.
- (b)
Decreased degradation of GABA by inhibiting GABA-T (GABA-transaminase) enzyme.
- (a)
Pharmacokinetics.
Valproate is rapidly and almost completely absorbed from the GI tract, highly (about 90%) bound to plasma proteins, metabolized in liver and excreted in urine.
Adverse effects (note the mnemonic valproate)
- 1.
The common side effects related to GI tract are nausea, V omiting, A norexia and abdominal discomfort.
- 2.
CNS side effects include sedation, ataxia and tremor.
- 3.
A rare but serious complication is fulminant hepatitis ( L iver), hence avoided in children younger than 3 years. Monitoring of hepatic function is essential during valproate therapy; E levation of liver enzymes occurs.
- 4.
T eratogenicity: O rofacial and digital abnormalities; neural tube defects with increased incidence of spina bifida, so it should not be given during pregnancy.
- 5.
The other adverse effects include skin R ashes, A lopecia and curling of hair; acute P ancreatitis may occur rarely.
Uses.
Sodium valproate is highly effective in absence, myoclonic, partial (SPS and CPS) and generalized tonic–clonic seizures. Other uses of valproate are mania, bipolar disorder and migraine prophylaxis.
Divalproex: It contains valproic acid and sodium valproate in 1:1 ratio. It is administered orally. It causes less GI side effects than valproic acid.
Diazepam, lorazepam, clonazepam (benzodiazepines)
Diazepam and lorazepam are effective in controlling status epilepticus. Intravenous diazepam is used in the emergency treatment of status epilepticus, tetanus, eclamptic convulsions, febrile convulsions, drug-induced convulsions, etc. Diazepam has a rapid onset but short duration of action; hence, repeated doses are required. Diazepam can be administered rectally in children during emergency. Lorazepam is preferred in status epilepticus because:
- 1.
It has a rapid onset and long duration of action.
- 2.
It has less damaging effect on injected vein.
Clonazepam, a long-acting BZD, is used in absence and myoclonic seizures.
Mechanism of action
(see p. 166)
Adverse effects.
Intravenous diazepam and lorazepam may cause hypotension and respiratory depression. The main side effects of clonazepam are sedation and lethargy, but tolerance develops on chronic therapy. Other side effects are hypotonia, dysarthria, dizziness and behavioural disturbances like irritability, hyperactivity and lack of concentration.
Newer antiepileptics
These are lamotrigine, topiramate, zonisamide, lacosamide, gabapentin, pregabalin, tiagabine, vigabatrin and levetiracetam. They are administered orally. Important features are given in Table 5.10 .
| Drugs | Mechanism of action | Uses | Adverse effects and other important points |
|---|---|---|---|
| Delays the recovery of Na + channels from inactivation | As monotherapy or add-on therapy in GTCS, absence, myoclonic and partial (SPS and CPS) seizures |
|
| Topiramate |
|
|
|
| Zonisamide | Delays the recovery of Na + channels from inactivation | As add-on drug in simple partial and complex partial seizures |
|
| Lacosamide | Delays the recovery of Na + channels from inactivation | As add-on drug in refractory partial seizures | Dizziness, diplopia, ataxia and cardiac arrhythmias |
| Gabapentin | Acts by releasing GABA |
|
|
| Pregabalin | Acts by releasing GABA | Useful in partial seizures and neuralgias | Skin rashes and sedation |
| Tiagabine | Inhibits the uptake of GABA into the neurons, thus, increases GABA activity | Used as add-on drug in partial seizures | Sedation, dizziness |
| Vigabatrin | Increases GABA activity in brain by inhibiting GABA transaminase | As an adjunct in partial seizures | Visual disturbances, sedation, confusion and psychosis |
| Levetiracetam | Not exactly known; binds to synaptic vesicle protein and modulates release of neurotransmitters like GABA | As an adjunct in GTCS, partial and myoclonic seizures | Sedation, dizziness and fatigue |
Status epilepticus
It is a medical emergency and should be treated immediately. It is characterized by recurrent attacks of tonic–clonic seizures without the recovery of consciousness in between or a single episode lasts longer than 30 minutes.
Treatment
- 1.
Hospitalize the patient.
- 2.
Maintain airway and establish a proper i.v. line.
- 3.
Administer oxygen.
- 4.
Collect blood for estimation of glucose, calcium, electrolytes and urea.
- 5.
Maintain fluid and electrolyte balance.
Dose and drug interactions of antiepileptics are summarized in Table 5.11 .
| Drug | Dose | Interactions |
|---|---|---|
|
|
|
|
|
|
| Phenobarbitone | 100–200 mg |
|
| Ethosuximide | 500–1500 mg |
|
| Sodium valproate | 1500–2000 mg |
|
Analgesics
Analgesics are drugs that relieve pain without significantly altering consciousness. They relieve pain without affecting its cause.
Opioid analgesics PH1.19
Morphine is the most important alkaloid of opium – the dried juice obtained from the capsules of Papaver somniferum . Opium contains many other alkaloids, e.g. codeine, thebaine, papaverine, etc. The term ‘opiates’ refers to drugs derived from opium poppy, whereas ‘opioid analgesic’ applies to any substance (endogenous peptides or drugs), which produces morphine-like analgesia.
Classification of opioids
- 1.
Opioid agonists
- (a)
Natural opium alkaloids: Morphine, codeine, thebaine,* papaverine,* noscapine.*
- (b)
Semisynthetic opiates: Heroin, pholcodine,* hydromorphone, oxymorphone.
- (c)
Synthetic opioids: Pethidine, tramadol, tapentadol, methadone, dextropropoxyphene, fentanyl, alfentanil, sufentanil, remifentanil.
- (a)
- 2.
Opioid agonist–antagonists: Pentazocine, butorphanol, nalorphine, nalbuphine.
- 3.
Partial μ-receptor agonist and κ-receptor antagonist: Buprenorphine.
Note: *Have no analgesic activity.
Opioid receptors
The three main types of opioid receptors are μ (mu), κ (kappa) and δ (delta). These receptor-mediated effects are given below.
μ: Analgesia (spinal + supraspinal level), respiratory depression, dependence, sedation, euphoria, miosis, decrease in GI motility.
κ: Analgesia (spinal + supraspinal level), respiratory depression, dependence, dysphoria, psychotomimetic effect.
δ: Analgesia (spinal + supraspinal level), respiratory depression, proconvulsant action.
Opioid agonists
Mechanism of action
Morphine and other opioids produce their actions by interacting with various opioid receptors – mu (μ), delta (δ) and kappa (κ). They are located at spinal, supraspinal (medulla, midbrain, limbic system and cortical areas) and peripheral nerves. Morphine is the prototype drug.
Pharmacological actions of morphine.
Morphine has mainly CNS-depressant effects but also has stimulant effects at certain sites in the CNS.
- 1.
CNS
- (a)
The depressant effects:
- (i)
Analgesic effect: Mediated mainly through μ-receptors at spinal and supraspinal sites (central action), it is the most important action of morphine. At the spinal level, it decreases release of excitatory neurotransmitters from primary pain afferents in substantia gelatinosa of dorsal horn. The excitability of neurons in dorsal horn is decreased. In the supraspinal level, it alters transmission of pain impulses. It is a very potent and efficacious analgesic. It causes sedation, drowsiness, euphoria, makes the person calm and raises the pain threshold. Perception of pain and reaction to it (fear, anxiety and apprehension) are altered by these drugs. Moderate doses of morphine relieve dull and continuous pain, whereas sharp, severe intermittent pain such as traumatic or visceral pain requires larger doses of morphine. Opioids also act peripherally to alter the sensitivity of small nerve endings in the skin to painful stimuli associated with tissue injury/inflammation.
- (i)
- (a)
Therefore, morphine relieves ‘total pain’.
- (ii)
Euphoria (feeling of well-being): It is an important component of analgesic effect. Anxiety, fear, apprehension associated with painful illness or injury are reduced by opioids.
- (iii)
Sedation: Morphine, in therapeutic doses, causes drowsiness and decreases physical activity.
- (iv)
Respiratory depression: It depresses respiration by a direct effect on the respiratory centre in the medulla; both rate and depth are reduced because it reduces sensitivity of respiratory centre to CO 2 . Respiratory depression is the commonest cause of death in acute opioid poisoning.
- (v)
Cough suppression: It has a direct action on cough centre in the medulla.
- (vi)
Hypothermia: In high doses, morphine depresses temperature-regulating centre and produces hypothermia.
- (b)
The stimulant effects:
- (i)
Miosis: Morphine produces constriction of pupils due to stimulation of III cranial nerve nucleus. Some tolerance develops to this action. Pinpoint pupils are an important feature in acute morphine poisoning. Miosis is not seen on topical application of morphine to the eye.
- (ii)
Nausea and vomiting: It is due to direct stimulation of the CTZ in medulla. 5-HT 3 antagonists are the drugs of choice to control opioid-induced nausea and vomiting. H 1 -blockers, such as cyclizine or prochlorperazine may also be used.
- (iii)
Vagal centre: It stimulates vagal centre in the medulla and can cause bradycardia.
- (i)
- (c)
Other effects:
Physical and psychological dependence: Repeated use of opioids causes physical and psychological dependence.
- 2.
CVS: Morphine produces vasodilatation and fall of BP.
It mainly causes vasodilatation of peripheral vessels, which results in shift of blood from pulmonary to systemic vessels leading to relief of pulmonary oedema associated with acute left ventricular failure.
- 3.
GIT: It causes constipation by direct action on GI tract and CNS – decreases GI motility and increases tone of the sphincters.
- 4.
Urinary bladder: It may cause urinary retention by increasing tone of urethral sphincter.
- 5.
Biliary tract: It increases intrabiliary pressure by increasing tone of sphincter of Oddi.
- 6.
Histamine release: Morphine is a histamine liberator and causes itching, skin rashes, urticaria, vasodilatation, bronchoconstriction, etc.
Pharmacokinetics.
On oral administration, morphine is absorbed slowly and erratically. It also undergoes extensive first-pass metabolism; hence, oral bioavailability of morphine is poor. Morphine is commonly administered by i.v., i.m. or s.c. routes. It can also be administered by oral, epidural or intrathecal routes. It is widely distributed in the body, crosses placental barrier and is metabolized in liver by glucuronide conjugation. Morphine-6-glucuronide has more potent analgesic action than morphine and is excreted in urine.
Adverse effects PH1.19
- 1.
Nausea, vomiting and constipation.
- 2.
Respiratory depression.
- 3.
Hypotension due to vasodilatation.
- 4.
Drowsiness, confusion and mental clouding.
- 5.
Itching (due to histamine release) and skin rashes.
- 6.
Difficulty in micturition.
- 7.
Respiratory depression in newborn due to administration of morphine to the mother during labour.
- 8.
Drug tolerance develops to most of the effects of morphine (some tolerance develops to miotic effect). There is cross-tolerance among the opioids.
- 9.
Seizure threshold is lowered.
- 10.
Drug dependence (physical and psychological dependence) is the main drawback of opioid therapy. Psychological dependence is associated with intense craving for the drug. Physical dependence is associated with the development of withdrawal symptoms (abstinence syndrome) when administration of an opioid is stopped abruptly. The symptoms and signs are irritability, body shakes, yawning, lacrimation, sweating, fever, diarrhoea, palpitation, insomnia, rise in BP, loss of weight, etc. (the symptoms are just opposite to morphine actions). Dependence is mediated through μ-receptors.
Treatment of morphine dependence:
- (a)
Hospitalization of the patient.
- (b)
Gradual withdrawal of morphine.
- (c)
Substitution therapy with methadone. Opioid agonist like methadone is preferred because:
- (i)
It is orally effective.
- (ii)
It has longer duration of action.
- (iii)
Withdrawal symptoms are mild.
1 mg of methadone will substitute 4 mg of morphine. Later, methadone is gradually reduced and completely stopped within 10 days. Buprenorphine can also be used for the treatment of opioid dependence.
- (i)
- (d)
Pure opioid antagonist like naltrexone is used after detoxification to produce opioid blockade to prevent relapse in patients who have a sincere desire to leave the habit. It is the preferred antagonist because it is orally effective and has a long duration of action.
- (e)
Psychotherapy, occupational therapy, community treatment and rehabilitation. PH1.23
- 11.
Acute morphine poisoning: The characteristic triad of symptoms are respiratory depression, pinpoint pupils and coma. The other signs and symptoms are cyanosis, hypotension, shock and convulsions. Death is usually due to respiratory depression.
Treatment of acute morphine poisoning:
- 1.
Hospitalization.
- 2.
Maintain airway, breathing and circulation.
- 3.
Ventilatory support (positive pressure respiration).
- 4.
Gastric lavage with potassium permanganate.
- 5.
Specific antidote: Naloxone 0.4–0.8 mg intravenously; dose is repeated till respiration becomes normal. Naloxone is a pure antagonist, competitively blocks opioid receptors and rapidly reverses the respiratory depression ( Fig. 5.10 ). The duration of action of naloxone is short; hence, repeated administration is needed.
Fig. 5.10 Competitive antagonism.
Note: Administration of naloxone to morphine addicts should be done with caution because it may precipitate severe withdrawal symptoms.
Contraindications
- 1.
Head injury: Morphine is contraindicated in cases with head injury because:
- (a)
Vomiting, miosis and mental clouding produced by morphine interfere with assessment of progress in head injury patients.
- (b)
Morphine → Respiratory depression → CO 2 retention → Cerebral vasodilation →↑↑ Intracranial tension.
- (a)
- 2.
Bronchial asthma: Morphine may cause severe bronchospasm due to histamine release.
- 3.
COPD: It should be avoided in patients with low respiratory reserve – emphysema, chronic bronchitis, cor pulmonale, etc.
- 4.
Hypotensive states: It should be used cautiously in shock or when there is reduced blood volume.
- 5.
Hypothyroidism and hypopituitarism: There is a prolonged and exaggerated response to morphine.
- 6.
Infants and elderly: They are more prone to respiratory depressant effect of morphine. In elderly male, there is an increased chance of urinary retention.
- 7.
Undiagnosed acute abdominal pain: Morphine, if given before diagnosis interferes with diagnosis by masking the pain. Its spasmogenic effect may aggravate the pain (biliary colic).
Codeine: Natural opium alkaloid
- 1.
Codeine has analgesic and cough-suppressant effects; it is administered orally.
- 2.
Compared to morphine:
- (a)
It is less potent and less efficacious as an analgesic.
- (b)
It has less respiratory depressant effect.
- (c)
It is less constipating.
- (d)
It has low addiction liability.
- (a)
- 3.
It has selective cough suppressant effect (antitussive), hence used to suppress dry cough.
- 4.
It potentiates analgesic effect of aspirin and paracetamol.
Codeine is used for relief of moderate pain. The main side effects are constipation and sedation.
Pholcodine:
See p. 255
Pethidine (meperidine) ( table 5.12 ).
Pethidine is a synthetic opioid; it has some anticholinergic actions. Dry mouth and tachycardia can occur.
| Morphine | Pethidine (Meperidine) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
It can be administered by oral, i.v., s.c. and i.m. routes. It is well absorbed from the GI tract, but bioavailability is about 50% because of first-pass effect; widely distributed in the body, crosses placental barrier and is metabolized in liver. The metabolites are excreted in urine.
Adverse effects.
The adverse effects of pethidine are similar to those of morphine. It can cause tremors, hallucinations, muscle twitches and rarely convulsions due to its metabolite, norpethidine. Tolerance, physical and psychological dependence can also develop with pethidine.
Diphenoxylate.
It is a pethidine congener and is useful in the treatment of diarrhoea. It is available in combination with atropine. It is rarely used at present because of its side effect (paralytic ileus).
Loperamide.
Loperamide is a pethidine congener. It reduces GI motility and secretions but increases the tone of anal sphincter. It is used in the symptomatic treatment of diarrhoea. Common side effects are constipation and abdominal cramps.
Therapeutic uses of opioids
- 1.
As analgesic ( Fig. 5.11 ) : Morphine and other opioids are potent and efficacious analgesics, hence used for moderate to severe painful conditions, such as acute myocardial infarction (MI), burns, pulmonary embolism, fracture mandible and long bones, bullet wound, etc. Opioids are also used to control severe pain in terminal stages of cancer. In renal and biliary colic, atropine is used with morphine to counteract spasmogenic effect of morphine. Opioids are the preferred analgesics in severe painful conditions (WHO analgesic ladder) ( Fig. 5.11 ).
Patient controlled analgesia : This allows the patient to control the delivery of s.c., epidural or i.v. analgesic in a safe and effective way through a pump. The patient should inform nurse when he or she takes a dose so that it can be replaced.
Fig. 5.11 World Health Organization analgesic ladder. (*Adjuvants, e.g. carbamazepine, amitriptyline, diazepam, prednisolone.) - 2.
Preanaesthetic medication: Opioids like morphine and pethidine are used about half an hour before anaesthesia because of their sedative, analgesic and euphoric effects; the dose of anaesthetic required is reduced.
- 3.
Acute pulmonary oedema (cardiac asthma): i.v. morphine relieves breathlessness associated with acute left ventricular failure due to pulmonary oedema by:
- (a)
Reducing preload on heart by peripheral vasodilatation.
- (b)
Shifting blood from pulmonary to systemic circulation.
- (c)
Reducing anxiety, fear and apprehension associated with illness.
- (a)
- 4.
Postanaesthetic shivering – pethidine is effective.
- 5.
Cough: Codeine and dextromethorphan are used for suppression of dry cough.
- 6.
Diarrhoea: Synthetic opioids such as loperamide and diphenoxylate are used for symptomatic treatment of diarrhoea.
Other opioids
The route of administration, uses and important features are represented in Table 5.13 .
| Opioid | Actions and uses | Important adverse effects | ||
|---|---|---|---|---|
|
|
| ||
| Analgesic – less potent than morphine |
| ||
|
| |||
|
|
| ||
|
|
| ||
|
|
| ||
|
|
| ||
|
|
| ||
|
|
| ||
Tramadol.
It is a synthetic codeine derivative with weak agonistic activity at μ-receptors. It also inhibits the reuptake of NA and 5-HT. It decreases seizure threshold.
Tapentadol.
It is a μ-agonist. It also predominantly inhibits reuptake of NE than 5-HT into the neurons. It is useful in mild to moderate pain. Adverse effects are similar to tramadol but vomiting is less.
Fentanyl.
It is a synthetic opioid with a potent μ-agonistic effect (100 times more potent than morphine as an analgesic).
Pharmacological actions are similar to morphine. Alfentanil, sufentanil and remifentanil are short-acting fentanyl analogues. They are useful for short procedures where intense analgesia is required.
Methadone.
It is a synthetic opioid with agonistic effect at μ-receptors and has a long duration of action. Pharmacological actions are similar to morphine.
Dextropropoxyphene.
It is structurally similar to methadone. The side effects are nausea, constipation, sedation, abdominal pain, etc. It may cause cardiotoxicity and pulmonary oedema.
Opioid agonist–antagonists and partial agonists
Pentazocine.
Pentazocine is an opioid agonist–antagonist. It has agonistic action at κ- and weak antagonistic action at μ-receptors. In low doses, its pharmacological actions are almost similar to that of morphine. In higher doses, it causes sympathetic stimulation.
Buprenorphine.
It is a partial μ-receptor agonist and κ-receptor antagonist; it is about 25 times more potent than morphine as analgesic. The pharmacological actions are qualitatively similar to morphine but it has a delayed onset and prolonged duration of action. It can be administered by parenteral and sublingual routes.
Opioid antagonists: Naloxone, naltrexone and nalmefene ( fig. 5.10 )
They are pure opioid antagonists. These drugs have no agonistic activity.
Naloxone, naltrexone and nalmefene competitively reverse the effects of both natural and synthetic opioids, but do not completely reverse buprenorphine-induced respiratory depression. Naloxone also blocks analgesic effect of placebo and acupuncture, and effects of endogenous opioid peptides. It is orally not effective because of high first-pass metabolism. It is short acting. On i.v. administration, it immediately antagonizes all the actions, especially respiratory depression, of morphine and other opioids. i.v. naloxone precipitates withdrawal symptoms in morphine and heroin addicts.
Uses of naloxone
- 1.
The main therapeutic use of naloxone is for the treatment of morphine and other opioid poisoning (see p. 205).
- 2.
In the treatment of opioid overdosage, i.v. naloxone rapidly reverses respiratory depression induced by opioids (except buprenorphine where it causes partial reversal of respiratory depression).
- 3.
To treat neonatal asphyxia due to use of opioids in the mother during labour.
Uses of naltrexone.
Naltrexone is orally more potent and has longer duration of action than naloxone .
- 1.
Naltrexone is used for opioid blockade therapy to prevent relapse in opioid-dependent individuals.
- 2.
It is also used for the treatment of alcoholism, as it reduces the urge to drink.
Methylnaltrexone , a derivative of naltrexone, has only peripheral actions. It can be used for treatment of constipation due to opioids.
Nalmefene
- ■
It is administered intravenously.
- ■
It is longer acting than naloxone.
- ■
It is useful in the treatment of opioid overdosage.
Endogenous opioid peptides
Endorphins, enkephalins and dynorphins are naturally occurring substances present in the brain and other body tissues. They are called endogenous opioid peptides because their effects are similar to opium alkaloids (e.g. morphine) in their actions. These peptides appear to be involved in placebo and acupuncture-induced analgesia.
Antiparkinsonian drugs PH1.19
Parkinson disease (PD) was first described by Sir James Parkinson. It is characterized by tremor, rigidity, bradykinesia (slowness of movements) and the loss of postural reflexes.
In idiopathic parkinsonism, there is degeneration of the dopamine-containing neurons in the substantia nigra, resulting in dopamine deficiency. Hence, the balance between inhibitory dopaminergic neurons and excitatory cholinergic neurons is disturbed resulting in relative cholinergic overactivity ( Fig. 5.12 ).
Classification
- 1.
Drugs influencing brain dopaminergic system:
- (a)
Dopamine precursor: Levodopa (L-Dopa).
- (b)
Dopamine agonists: Bromocriptine, pramipexole, ropinirole.
- (c)
NMDA-receptor antagonist: Amantadine.
- (d)
Monoamine oxidase (MAO)-B inhibitors: Selegiline (deprenyl), rasagiline.
- (e)
Catechol-O-methyltransferase (COMT) inhibitors: Tolcapone, entacapone.
- (a)
- 2.
Drugs influencing brain cholinergic system
- (a)
Centrally acting anticholinergic drugs: Benztropine, benzhexol (trihexyphenidyl), procyclidine, biperiden.
- (b)
Antihistaminics (H 1 -blockers) with anticholinergic activity: Promethazine, diphenhydramine, orphenadrine.
- (a)
The main aim of drug therapy in parkinsonism is to either enhance dopamine activity or reduce cholinergic activity in the striatum.
Dopamine precursor: Levodopa
L-Dopa is the main drug for the treatment of idiopathic parkinsonism. Dopamine does not cross BBB; hence, its immediate precursor L-Dopa (prodrug) is used. It is converted to dopamine by decarboxylase enzyme in the dopaminergic neurons of the striatum. Dopamine produced then interacts with D 2 -receptors in the basal ganglia to produce antiparkinsonian effect. In early stages of the disease, improvement is almost complete. All the clinical symptoms (rigidity, bradykinesia and tremor) of parkinsonism improve, but the progression of the disease is not stopped. A large amount of the drug is converted to dopamine in the peripheral tissues by peripheral decarboxylase enzyme. Only a small amount (2%–3%) of L-Dopa enters the brain. Therefore, L-Dopa is used in combination with carbidopa/benserazide (peripheral decarboxylase inhibitor) which does not cross the BBB; the peripheral metabolism of L-Dopa is reduced, thus increasing its bioavailability in the basal ganglia ( Fig. 5.13 ).
Pharmacokinetics.
On oral administration, L-Dopa is rapidly absorbed from the small intestine by an active transport system. Amino acids present in food may interfere with the absorption of L-Dopa; hence, it should be given 30–60 minutes before meal. Active transport of L-Dopa into the brain may be inhibited by competition from dietary amino acids. The main metabolic products of L-Dopa are homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) ( Fig. 5.14 ). The metabolites are excreted in urine.
Adverse effects
- 1.
GIT: Nausea, vomiting and anorexia are common during initial treatment with L-Dopa. Tolerance to emetic effect develops slowly.
- 2.
CVS: The commonest cardiovascular side effect is postural hypotension, which is usually asymptomatic. It can also cause tachycardia, palpitation and rarely cardiac arrhythmias.
- 3.
Dyskinesias (abnormal involuntary movements): Tics, tremors and choreoathetoid movements may occur. Tolerance does not develop to abnormal movements.
- 4.
Alteration in taste sensation.
- 5.
Mental changes like insomnia, confusion, delusions, euphoria, depression, anxiety, hallucinations and nightmares.
- 6.
Fluctuations in response: After 3–5 years of therapy, with progressing disease, control becomes poor and fluctuations in symptoms occur frequently. Wearing off (end-of-dose) is due to decrease in plasma concentration of L-Dopa towards the end-of-a-dose interval. Patient may show fluctuation in response – being ‘off’ (loss of beneficial effect of the drug) and being ‘on’ (relief of most of the symptoms but with disabling dyskinesias) called the on/off phenomenon. Sustained release formulation of L-Dopa –carbidopa produces more stable plasma L-Dopa levels and helps to reduce fluctuation in response (on/off phenomena). End-of-dose deterioration can also be improved by administering L-Dopa in smaller and more frequent doses.
Peripheral decarboxylase inhibitors: Carbidopa and benserazide
Carbidopa and benserazide are peripheral decarboxylase inhibitors. These drugs do not cross BBB. L-Dopa is always given in combination with carbidopa/benserazide. The currently used combinations are as follows:
- ■
L-Dopa + carbidopa (4:1 or 10:1 ratio).
- ■
L-Dopa + benserazide (4:1 ratio).
The advantages of these fixed-dose combinations are as follows:
- 1.
Increased bioavailability of dopamine in the basal ganglia ( Fig. 5.13 ). Hence, the dose of L-Dopa can be reduced by 75%.
- 2.
Prolongation of plasma half-life of L-Dopa.
- 3.
Reduction in the incidence of GI side effects like nausea and vomiting.
- 4.
Cardiovascular side effects like tachycardia, hypotension and cardiac arrhythmias are minimized.
- 5.
Better patient compliance.
- 6.
Sustained release preparation of L-Dopa –carbidopa helps to reduce on/off phenomenon.
Dopamine-receptor agonists: Bromocriptine, ropinirole and pramipexole
These drugs have direct action on dopamine receptors. Like L-Dopa, they can relieve signs and symptoms of parkinsonism. They are administered orally. The duration of action of these drugs is longer than that of L-Dopa and these are used particularly in patients who have frequent fluctuation of symptoms (on/off phenomena).
Bromocriptine.
Bromocriptine is an ergot derivative; it has agonistic action at D 2 - and partial agonist at D 1 -receptors.
Adverse effects.
Adverse effects include anorexia, nausea, vomiting, constipation, postural hypotension, cardiac arrhythmias, digital vasospasm, dyskinesias, headache, confusion, hallucinations and nasal congestion. It is contraindicated in patients with history of mental illness, recent MI, peptic ulcer and peripheral vascular diseases.
Ropinirole and pramipexole.
These are nonergoline derivatives; hence, ergot-related side effects are not seen. These drugs are often used in the initial treatment of parkinsonism. They can be used as monotherapy in mild parkinsonism or in combination with L-Dopa –carbidopa. They also exert neuroprotective effect. Dyskinesias and fluctuation in response are less with these drugs than L-Dopa. The other indication of these nonergolines is in ‘restless leg syndrome’.
Adverse effects.
Nausea, vomiting, confusion, fatigue, somnolence, hallucinations, postural hypotension, dyskinesia and rarely, sudden attacks of irresistible sleep during day time. GIT side effects are lower as compared to bromocriptine.
COMT inhibitors: Tolcapone, entacapone
Tolcapone and entacapone are reversible COMT inhibitors. By inhibiting the peripheral metabolism of L-Dopa to 3- O- methyldopa, they increase the half-life of L-Dopa and also enhance its bioavailability in the CNS. The ‘on’ time is prolonged and the dose of L-Dopa can be reduced. Tolcapone has both peripheral and central actions with relatively longer duration of action, whereas entacapone inhibits COMT only in the periphery ( Fig. 5.14 ). These drugs are used as adjunct to L-Dopa –carbidopa for advanced cases of PD. Combined preparation of L-Dopa + carbidopa + entacapone is available.
Adverse effects.
These include dyskinesia, nausea, diarrhoea, confusion, hypotension and hallucinations. Tolcapone may rarely cause fulminant hepatitis; hence, it should be avoided in patients with liver disease. Entacapone does not cause hepatotoxicity.
MAO-B inhibitors: Selegiline (deprenyl) and rasagiline
They selectively and irreversibly inhibit MAO-B enzyme in the brain ( Fig. 5.14 ). They are administered orally. They do not inhibit MAO in the periphery. They retard the metabolism of DA in the brain and prevent the formation of toxic metabolites. Thus, they produce neuroprotective effect in idiopathic PD and retard the progression of disease. They are used as an adjunct with L-Dopa. They enhance as well as prolong the effect of L-Dopa, thus reducing the dose of L-Dopa required. They also reduce ‘on-off’ and ‘wearing off’ phenomena. Rasagiline is more potent and longer acting than selegiline; hence, single daily dose is adequate. The metabolites of selegiline are amphetamine and methamphetamine which cause side effects like insomnia, anxiety, nausea and vomiting.
NMDA-receptor antagonist: Amantadine
Amantadine is an antiviral drug used for the treatment and prophylaxis of influenza A. It is also used in parkinsonism. It facilitates the synthesis and release of dopamine from dopaminergic neurons in the brain. It also has NMDA-receptor antagonist action – decreases glutamate neurotransmission in the basal ganglia which could contribute to its beneficial effect in parkinsonism. It is less effective than L-Dopa and hence used for the initial treatment of mild parkinsonism. Its therapeutic activity may be increased by combining with L-Dopa. It is given by oral route and is well tolerated.
Adverse effects.
They include headache, heart failure, hypotension, hallucinations, nausea, vomiting, constipation, dry mouth, insomnia and livedo reticularis (discoloured patches on the skin).
Central anticholinergics
Centrally acting anticholinergics like benzhexol (trihexyphenidyl) and benztropine are the treatment of choice in drug-induced parkinsonism and are also effective in idiopathic parkinsonism. They have mainly central anticholinergic action with minimal peripheral action. They act by reducing the increased cholinergic activity in the striatum. They are less effective than L-Dopa, but are cheap and better tolerated. They are mainly effective in relieving tremor and rigidity of parkinsonism with little effect on hypokinesia. Adverse effects are dry mouth, confusion, constipation, blurring of vision, drowsiness, hallucinations and urinary retention.
Antihistaminics with anticholinergic action like promethazine, diphenhydramine and orphenadrine are also effective in decreasing cholinergic overactivity in basal ganglia.
L-Dopa is not effective in drug-induced parkinsonism, because:
- (a)
Dopamine receptors are blocked.
- (b)
There is no deficiency of dopamine.
- (a)
Drug interactions
- 1.
L-Dopa × MAO inhibitors (nonselective): Inhibition of MAO retards the metabolism of dopamine → plasma concentration of dopamine increases → may precipitate hypertensive crisis.
- 2.
L-Dopa × pyridoxine: Pyridoxine promotes the peripheral conversion of L-Dopa to dopamine and reduces the therapeutic effect of L-Dopa.
- 3.
L-Dopa × antihypertensive agents: Worsening of postural hypotension.
- 4.
L-Dopa × metoclopramide: Metoclopramide crosses the BBB, blocks the D 2 -receptors in the basal ganglia and causes drug-induced parkinsonism (i.e. interferes with antiparkinsonian effect of L-Dopa); domperidone poorly crosses BBB; hence, there is no interference with therapeutic effect of L-Dopa.
Drugs for Alzheimer’s Disease
It is a degenerative disease of the cerebral cortex with decreased cholinergic transmission. Drugs used are donepezil, galantamine and rivastigmine. They are cerebroselective anticholinesterases. They increase cerebral levels of acetylcholine and have shown to produce some benefit in these patients. Other drugs used are memantine (NMDA-receptor antagonist), Ginkgo biloba, etc.
Cognitive enhancers (nootropics) PH1.19
Cognition enhancers are drugs which help to reduce the impairment of cognitive functions associated with age, head injury, stroke and neurodegenerative disorders. They improve memory ( Table 5.14 ).
| Drug | Route of administration | Mechanism of action | Uses | Adverse effects |
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CNS stimulants PH1.19, PH1.22
Some of the CNS stimulants are given in Table 5.15 .
| Drug | Route of administration | Action | Uses | Adverse effects |
| Doxapram | Intravenous infusion |
|
| Nausea, vomiting, arrhythmias |
| Modafinil | Oral |
| Narcolepsy | Headache |
| Oral |
| ADHD, narcolepsy | Insomnia, tachycardia, palpitation |
| Methylphenidate | Oral |
| ADHD | Suppression of appetite, weight loss |
Atomoxetine
- ■
Norepinephrine reuptake inhibitor (not a CNS stimulant).
- ■
Route of administration – oral; used in the treatment of attention deficit hyperactivity disorder (ADHD) – increases ability to pay attention and decreases hyperactivity.
- ■
Adverse effects include insomnia, gastrointestinal side effects; rarely, suicidal ideas.
Psychopharmacology PH1.19
The major types of psychiatric illnesses are psychoses and neuroses ( Table 5.16 ).
| Psychoses | Neuroses |
|
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|
|
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|
|
|
Antipsychotic drugs PH1.19
Antipsychotic drugs are also known as neuroleptic drugs or antischizophrenic drugs. Neuroleptic drugs are mainly used in schizophrenia, acute mania and other acute psychotic states.
Classification
- 1.
Phenothiazines: Chlorpromazine, triflupromazine, trifluoperazine, thioridazine, fluphenazine
- 2.
Thioxanthenes: Flupenthixol
- 3.
Butyrophenones: Haloperidol, trifluperidol
- 4.
Atypical antipsychotics: Risperidone, clozapine, olanzapine, quetiapine, zotepine, aripiprazole, amisulpride, ziprasidone
- 5.
Others: Loxapine, pimozide
Mechanism of action of antipsychotics
- ■
Conventional antipsychotics → Mainly block dopamine (D 2 )-receptors in the limbic system and mesocortical areas.
- ■
Atypical antipsychotics → Block 5-HT 2 receptors in mesolimbic system.
Chlorpromazine (phenothiazines)
Chlorpromazine is the prototype drug.
Pharmacological actions of chlorpromazine ( fig. 5.15 )
- ■
Central nervous system: In patients with schizophrenia, chlorpromazine:
- (a)
Reduces agitation and aggressiveness.
- (b)
Reduces spontaneous movements.
- (c)
Suppresses hallucinations and delusions.
- (d)
Relieves anxiety.
- (e)
Corrects disturbed thought and behaviour.
- (f)
Does not affect intelligence but impairs vigilance.
- (a)
- ■
Endocrine: Prolactin secretion is under the control of prolactin-releasing factor (PRF) and prolactin-inhibitory factor (PIF). PIF itself is dopamine; hence, the blockade of DA-receptors in pituitary may cause increased production of prolactin leading to galactorrhoea, amenorrhoea and infertility in females; gynaecomastia in males.
- ■
Other actions ( Fig. 5.15 ).
- ■
Tolerance to sedative and hypotensive actions develops within a few weeks.
Pharmacokinetics.
Phenothiazines are effective orally and parenterally. Chlorpromazine is highly bound to plasma proteins – reaches high concentration in the brain. It is metabolized in liver and excreted in urine.
Adverse effects of antipsychotics
Important side effects of these drugs are dose-dependent EPS.
- 1.
Parkinsonism: They are tremors, rigidity, hypokinesia, etc. Centrally acting anticholinergics (benzhexol, benztropine and antihistamines like promethazine, diphenhydramine, etc.) are effective in controlling these symptoms.
- 2.
Acute dystonias: Sudden onset of muscle spasms resulting in uncontrolled muscular movements involving the face, tongue, neck, etc. It responds to centrally acting anticholinergics, e.g. benzhexol.
- 3.
Akathisia: Feeling of restlessness – the person cannot sit at a place and has a desire to move about. It is treated with a BZD (e.g. clonazepam) or β-blocker (e.g. propranolol) or centrally acting anticholinergic.
- 4.
Neuroleptic malignant syndrome: It is a rare but serious complication, characterized by muscular rigidity, hyperpyrexia, mental confusion and coma. It is treated with i.v. dantrolene.
- 5.
Tardive dyskinesia ( Tardive – late occurring): It is characterized by involuntary movements of the mouth, tongue and the upper limbs. It develops in about 20% of patients after months or years of antipsychotic treatment. Treatment is usually unsuccessful.
- 6.
Muscarinic, α 1 -adrenergic and H 1 -receptor–blocking side effects ( Fig. 5.15 ).
- 7.
Weight gain is common with clozapine and olanzapine.
- 8.
Endocrine side effects are due to increased prolactin level resulting in amenorrhoea, galactorrhoea and infertility in females; gynaecomastia in males. Hyperglycaemia and precipitation of diabetes can occur with chlorpromazine.
- 9.
Hypersensitivity reactions can occur – skin rashes, itching, dermatitis, leucopenia and rarely obstructive jaundice. Agranulocytosis is a serious adverse effect with clozapine.
Haloperidol (butyrophenone)
- 1.
Widely used antipsychotic drug; pharmacological actions are similar to chlorpromazine
- 2.
Causes severe EPS.
- 3.
Has less seizure potential.
- 4.
Does not cause weight gain.
- 5.
Does not cause hyperglycaemia and dyslipidaemia.
- 6.
Rarely causes jaundice.
- 7.
Preferred agent for acute schizophrenia, acute mania, senile psychoses, Huntington disease, etc.
Atypical antipsychotics ( table 5.17 )
These drugs exert antipsychotic effect mainly by 5-HT 2 blockade. They have weak D 2 -blocking effects – low risk of EPS.
| Drug | Receptor | Actions |
| Chlorpromazine | Potent D 2 -blockade M, H 1 and α-blockade |
|
| Haloperidol, fluphenazine | Potent D 2 -blockade M, H 1 and α-blockade |
|
| Clozapine | Potent 5-HT 2 blockade D 2 - (weak), M, H 1 and α-blockade |
|
| Olanzapine | Potent 5-HT 2 blockade D 2 - (weak), M, H 1 and α-blockade |
|
| Risperidone | 5-HT 2 blockade D 2 -, M, H 1 and α-blockade |
|
| Ziprasidone | 5-HT 2 , D 2 -blockade |
|
| Aripiprazole | 5-HT 2 blockade D 2 partial agonist |
|
| Quetiapine | 5-HT 1A , 5-HT 2 , D 2 -blockade |
|
| Amisulpride | D 2 -blockade |
|
Clozapine and olanzapine
- 1.
Atypical antipsychotic drugs.
- 2.
Mainly block 5-HT 2 receptors.
- 3.
Have weak D 2 -blocking effect.
- 4.
Also block α 1 -receptors, H 1 - and muscarinic receptors.
- 5.
Cause sedation and hypotension.
- 6.
Rarely cause EPS.
Adverse effects ( table 5.17 )
Side effects of clozapine are sedation, salivation, seizures, weight gain and hypotension. The dangerous side effect is agranulocytosis; hence, regular monitoring of blood counts is required during clozapine therapy. Side effects of olanzapine are dry mouth, constipation, weight gain and rarely EPS. It does not cause agranulocytosis.
Uses.
Clozapine is a reserve drug for the treatment of schizophrenia because of the risk of agranulocytosis. Olanzapine is used for the treatment of schizophrenia and mania associated with bipolar disorder. They suppress both positive symptoms (thought disorder, hallucinations, delusions, etc.) and negative symptoms (social withdrawal, lack of motivation and flattening of emotions) of schizophrenia.
Risperidone
- 1.
Atypical antipsychotic drug.
- 2.
Blocks D 2 -, 5-HT 2 , α 1 -adrenergic and H 1 -receptors.
- 3.
EPS is rare at low doses.
- 4.
Used for the treatment of schizophrenia and short-term treatment of mania associated with bipolar disorder.
Other atypical antipsychotics are aripiprazole, ziprasidone, quetiapine and amisulpride ( Table 5.17 ).
Therapeutic uses
- 1.
Schizophrenia: The neuroleptics are the only efficacious drugs available for the treatment of schizophrenia (for effects in schizophrenia, see p. 218).
The atypical antipsychotics are commonly prescribed owing to the lower risk of EPS. Risperidone, olanzapine, aripiprazole, ziprasidone and quetiapine are frequently used. Clozapine is reserved for resistant cases of schizophrenia. Of the older agents, haloperidol and fluphenazine are commonly used.
- 2.
Mania: Acute mania can be treated with a neuroleptic (chlorpromazine or haloperidol); lithium is used for maintenance therapy. Atypical antipsychotics like olanzapine, risperidone, quetiapine and aripiprazole are commonly used for acute mania. If parenteral therapy is required, older agents like chlorpromazine or haloperidol are used.
- 3.
As antiemetic: These drugs (phenothiazines, haloperidol, etc.) produce antiemetic effect by blocking D 2 -receptors in CTZ. However, they are not routinely used as antiemetics because of their side effects. Phenothiazine, such as prochlorperazine, is useful for prevention and treatment of nausea and vomiting associated with migraine or emesis due to anticancer drugs.
- 4.
Intractable hiccough has been treated with chlorpromazine.
- 5.
As adjuvant with selective serotonin reuptake inhibitors (SSRIs) in anxiety.
Antianxiety agents PH1.19
- 1.
Benzodiazepines (BZDs): BZDs are the preferred anxiolytic drugs. Chlordiazepoxide, diazepam, lorazepam, oxazepam, alprazolam, nitrazepam, flurazepam, etc. are used as anxiolytic agents. They act on limbic system and facilitate the inhibitory effect of GABA. BZDs are mainly useful for short-term treatment of anxiety. They act rapidly and are most commonly used for acute anxiety. Adverse effects are sedation, impairment of memory, confusion and dependence. Tolerance may develop to anxiolytic effect on long-term use.
- 2.
Buspirone: Buspirone is a partial agonist of 5-HT 1A receptor and causes selective anxiolytic effect. It has no sedative, anticonvulsant or muscle relaxant effects. It does not potentiate the central effects of alcohol or other CNS depressants. There is no tolerance or drug dependence. It does not affect GABA transmission. Buspirone is well absorbed from GI tract; but bioavailability is low because of first-pass metabolism. It produces active metabolites. Enzyme inducers (rifampin) and inhibitors (erythromycin) alter its plasma levels. It is mainly used in the treatment of generalized anxiety states. But its effect is delayed and may take 2 weeks to fully develop. So, it is not effective for acute cases.
- 3.
β-Blockers: Propranolol and other nonselective β-blockers are used mainly to reduce the symptoms of anxiety, such as tachycardia, palpitation, tremor and sweating.
- 4.
SSRIs and serotonin and noradrenaline reuptake inhibitor (SNRI, venlafaxine): These are the preferred agents for most of the anxiety disorders, except acute anxiety. Response is delayed.
- 5.
H 1 -blocker: Hydroxyzine is a highly sedative first-generation H 1 -blocker; it has selective antianxiety action. It also has antiallergic, antiemetic and anticholinergic actions.
Antidepressants PH1.19
Depression is a common clinical condition associated with feeling of sadness, loss of interest, self-neglect, anorexia, sleep disturbances, suicidal feelings in severe cases, etc. Various hypotheses have been proposed for pathogenesis of depression.
- ■
Decrease in levels or function of monoamines (5-HT, NE, DA) in cortical and limbic system.
- ■
Decrease in brain-derived neurotrophic factor (BDNF).
- ■
Abnormalities in HPA axis, thyroid function and sex steroid levels.
Classification
- 1.
Tricyclic antidepressants (mnemonic: ANTI-DEP C)
A mitriptyline, Amoxapine D oxepin, Desipramine, Dothiepin N ortriptyline E ——————- T rimipramine P rotriptyline I mipramine C lomipramine - 2.
Selective serotonin (5-HT) reuptake inhibitors (SSRIs): Fluoxetine, fluvoxamine, citalopram, escitalopram, sertraline, paroxetine, dapoxetine.
- 3.
SNRIs: Duloxetine, venlafaxine.
- 4.
Atypical antidepressants: Trazodone, bupropion, mianserin, mirtazapine, atomoxetine.
- 5.
MAO-A inhibitors: Moclobemide, clorgyline.
Tricyclic antidepressants
Mechanism of action and actions are described in Fig. 5.16
Pharmacokinetics.
TCAs are well absorbed through the GI tract and are highly bound to plasma proteins. They are widely distributed in tissues including CNS. They are metabolized in liver. Some of them (imipramine, amitriptyline, etc.) produce active metabolites which are responsible for the long duration of action of these drugs. These drugs are excreted mainly in urine as inactive metabolites.
Adverse effects and contraindications of tricyclic antidepressants ( fig. 5.16 )
- 1.
‘Atropine-like’ side effects: Dryness of mouth, blurring of vision, constipation, urinary retention, etc.
- 2.
α 1 -Adrenergic blocking effects: Postural hypotension, tachycardia, cardiac arrhythmias, etc.
- 3.
H 1 -blocking effects: Sedation and confusion.
- 4.
Other effects: Increased appetite, weight gain and may precipitate convulsions (seizure threshold is lowered).
TCAs are contraindicated in patients with glaucoma, epilepsy, ischaemic heart disease and enlarged prostate.
Other antidepressants are shown in Table 5.18 .
| Drug | MOA | Other points |
|---|---|---|
|
|
|
| Inhibit serotonin transporter (SERT) → block reuptake of 5-HT into the neuron → increase the availability of 5-HT at receptors in the CNS and enhance serotoninergic activity |
|
| Inhibit the reuptake of serotonin and noradrenaline into the neuron (serotonin and norepinephrine reuptake inhibitors) |
|
| Inhibits the reuptake of DA and NA into the neuron |
|
| Blocks α 2 -autoreceptors on noradrenergic neurons and heteroreceptors on 5-HT neurons; increases NA and 5-HT release; also blocks H 1 -receptors |
|
| Blocks 5-HT reuptake and 5-HT 2 antagonist; blocks α 1 -adrenergic receptors |
|
| Increases NA release by blocking presynaptic α 2 -receptors |
|
MAO inhibitors
MAO is a mitochondrial enzyme involved in the metabolism of biogenic amines. There are two isoforms of MAO. MAO-A is responsible mainly for the metabolism of NA, 5-HT and tyramine. MAO-B is more selective for dopamine metabolism.
Moclobemide.
A selective and reversible inhibitor of MAO-A (RIMA) is relatively free of food and drug interactions. Hence, cheese reaction is rare. It is also devoid of anticholinergic, α 1 -adrenergic blocking and sedative effects.
Drug interactions
- (a)
Involving TCAs.
- (b)
Serotonin syndrome: Concomitant administration of SSRIs with MAO inhibitors produces severe undesirable effects like tremor, restlessness, muscle rigidity, hyperthermia, sweating, shivering, seizures and coma due to increased serotonin levels at the synapses, which is termed serotonin syndrome.
- (c)
SSRIs inhibit metabolism of a number of drugs such as TCAs, antipsychotics, β-blockers, phenytoin and carbamazepine, and increase their plasma levels.
Cheese reaction
Normally, tyramine in food is metabolized by MAO present in the gut and liver. So, very little tyramine reaches systemic circulation. When a patient on MAO inhibitor consumes food stuff rich in tyramine, it may result in fatal hypertensive crisis and cerebrovascular accidents. The reaction can be treated with i.v. phentolamine ( Fig. 5.17 ).
Uses of antidepressants
- 1.
Depression: Antidepressants are used in the treatment of endogenous depression (major depression) and during the phase of depression in bipolar illness. Patient starts taking interest in daily activities, mood is elevated, concentration improves and agitation decreases. Patient becomes more responsive. SSRIs are preferred to TCAs because of:
- (a)
Better tolerability.
- (b)
Less side effects (do not cause hypotension and sedation; do not have anticholinergic effects and no precipitation of convulsions, do not cause cardiac arrhythmias).
- (c)
Longer duration of action.
- (a)
- 2.
Anxiety disorders: SSRIs are used for the treatment of generalized anxiety disorder. Onset of action is slow; hence, BZDs are co-administered for a short period to control anxiety during this period. SNRIs like venlafaxine and duloxetine are also useful in anxiety.
- 3.
Obsessive compulsive disorder (OCD): Clomipramine (TCA) and fluvoxamine (SSRI) are highly effective.
- 4.
ADHD: TCAs (imipramine, nortriptyline, etc.) are used in ADHD. Atomoxetine, methylphenidate and dextroamphetamine can also be used in this disorder.
- 5.
Nocturnal enuresis: Imipramine is effective.
- 6.
Prophylaxis of migraine: Amitriptyline is effective.
- 7.
Chronic pain including neuralgias: TCAs are effective in trigeminal, herpetic and postherpetic neuralgias. Venlafaxine and duloxetine (SNRIs) are used in the treatment of fibromyalgia.
- 8.
Atopic dermatitis: Topical doxepin is useful; it has antipruritic action.
- 9.
Premature ejaculation: SSRIs like paroxetine, fluoxetine, sertraline citalopram and dapoxetine are effective. Dapoxetine is taken 1 hour before intercourse as it acts rapidly. If SSRIs are not tolerated, TCA like clomipramine can be used.
Drugs for bipolar disorder PH1.19
Bipolar disorder (manic-depressive illness) is a psychiatric disorder in which depression alternates with mania. Mania is an affective disorder that manifests as elation, agitation, hyperactivity, uncontrolled thought and speech.
Drugs used in bipolar disorder are lithium, carbamazepine, sodium valproate, olanzapine, risperidone, haloperidol, etc.
Lithium
Lithium was the first drug used for the treatment of mania. The antiepileptic drugs such as carbamazepine, sodium valproate and gabapentin have been approved for the treatment of bipolar disorder.
Actions and mechanism
Lithium reduces motor activity, decreases euphoria, relieves insomnia and stabilizes the mood in patient with bipolar disorder.
In the neuronal membrane:
IP 2 , inositol bisphosphate; IP 1 , inositol monophosphate; IP 3 , inositol triphosphate, DAG, diacylglycerol.
- 1.
Lithium, by inhibiting the above steps, reduces the release of IP 3 and DAG, which are second messengers for both α-adrenergic and muscarinic transmission.
- 2.
Lithium is a monovalent cation that can mimic the role of Na + .
- 3.
Lithium also decreases the release of NA and DA in the brain.
Other actions
- ■
Lithium may produce nephrogenic diabetes insipidus by blocking the action of ADH on collecting duct.
- ■
Increases total WBC count (leukocytosis).
- ■
Inhibits the release of thyroid hormones (T 3 and T 4 ).
Pharmacokinetics
Lithium carbonate is effective orally, does not bind to plasma proteins and is distributed throughout the total body water. It is not metabolized and gets excreted in urine, saliva, sweat, etc. Lithium is a monovalent cation. The kidney handles lithium in the same way as Na + . About 80% of the filtered lithium is reabsorbed in the proximal tubules. Sodium depletion reduces the rate of excretion of lithium and increases its toxicity. Lithium has low therapeutic index; hence, therapeutic drug monitoring (TDM) is essential for optimal therapy (normal levels: 0.5–1.5 mEq/L). Estimation of salivary concentration can be used for noninvasive monitoring of lithium.
Adverse effects
- 1.
GIT: Nausea, vomiting and diarrhoea.
- 2.
CNS: Tremor, ataxia, drowsiness, headache, muscular weakness and slurred speech.
- 3.
Renal: Polyuria, polydipsia due to inhibition of ADH action.
- 4.
Goitre with hypothyroidism may occur.
- 5.
Acute lithium toxicity manifests as confusion, convulsions, cardiac arrhythmias, coma and death.
Treatment
- 1.
Lithium should be stopped immediately, and its serum level is estimated.
- 2.
i.v. mannitol to promote lithium excretion.
- 3.
i.v. normal saline to restore Na + levels, which in turn promotes the excretion of lithium.
- 4.
Haemodialysis is indicated if the serum levels are very high (>4 mEq/L).
Uses of lithium
It is used as a prophylactic agent for bipolar disorder. It decreases the frequency and severity of both manic and depressive attacks; hence, it is called mood stabilizer. Lithium has a slow onset of action, hence not used for acute mania. Lithium is also useful in the prophylaxis of unipolar depression.
Drug interactions
- 1.
Lithium × thiazides/furosemide: Thiazides and furosemide cause hyponatraemia. As a result, there will be a compensatory increase in the reabsorption of Na + in PCT. Along with Na + , reabsorption of lithium is also increased leading to toxicity.
- 2.
Neuromuscular blockade induced by depolarizing (succinylcholine) and nondepolarizing (pancuronium) neuromuscular blockers is prolonged in patients on lithium.
- 3.
Lithium × haloperidol: Long-term lithium therapy may cause rigidity and potentiates the EPS of haloperidol.
Other drugs used in mania and bipolar disorder
- ■
Sodium valproate: It is the preferred drug for treatment of acute mania because of its rapid action, wider therapeutic index and better tolerability than lithium. It is also used prophylactically for bipolar disorder. It is used in combination with lithium or an antipsychotic. Divalproex can also be used.
- ■
Carbamazepine: Carbamazepine, an antiepileptic drug, has mood-stabilizing effect and is used in the treatment of bipolar disorder. It may be used alone or in combination with lithium or valproate. It is less effective than valproate/lithium. It is used prophylactically in bipolar disorder as adjunct to lithium.
- ■
Antipsychotics: Olanzapine, risperidone, aripiprazole, quetiapine, etc. are preferred agents to control acute attack of mania. They can be used alone or combined with BZD/sodium valproate/lithium in acute mania. Conventional antipsychotics like haloperidol and fluphenazine are also useful.
- ■
Lamotrigine, newer antiepileptic agent, is found to be useful only for prophylaxis of depression in bipolar disorder. It can also be used with lithium.
- ■
BZDs like lorazepam or clonazepam are used as adjuncts if patient is agitated.
*Mnemonic for actions of morphine: ‘MARPHINE CVS’.